Pyrazole derivatives, their preparation and their use in pharmaceuticals

ABSTRACT

The present invention relates to pyrazole derivatives of the formula I, their preparation and their use in pharmaceuticals: 
                 
 
in which X, R 1 , R 1a , R 2 , R 3 , R 4  and n are as defined in the claims, which are useful pharmaceutically active compounds for the therapy and prophylaxis of illnesses, for example of cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I are capable of modulating the body&#39;s production of cyclic guanosine monophosphate “cGMP” and are generally suitable for the therapy and prophylaxis of illnesses which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of the formula I, to their use for the therapy and prophylaxis of the abovementioned illnesses and for preparing pharmaceuticals for this purpose, and also to pharmaceutical preparations which comprise the compounds of the formula I.

This application is a continuation of application Ser. No. 09/702,669,filed Nov. 1, 2000, now abandoned, which is a division of applicationSer. No. 09/166,283, filed Oct. 5, 1998, now U.S. Pat. No. 6,162,819,which in turn claims the benefit of priority of German application19744026.6, filed Oct. 6, 1997, and incorporates by reference each ofthe foregoing applications.

The present invention relates to pyrazole derivatives of the formula I

in which X, R¹, R^(1a), R², R³, R⁴, and n are as defined below, whichderivatives are useful pharmaceutically active compounds for the therapyand prophylaxis of illnesses, for example cardiovascular diseases suchas hypertension, angina pectoris, cardiac insufficiency, thromboses, oratherosclerosis. The compounds of the formula I are capable ofmodulating the body's production of cyclic guanosine monophosphate“cGMP” and are generally suitable for the therapy and prophylaxis ofillnesses which are associated with a disturbed cGMP balance. Theinvention furthermore relates to processes for preparing compounds ofthe formula I, to their use for the therapy and prophylaxis of theabovementioned illnesses, to the methods of preparing pharmaceuticalsfor this purpose, and also to pharmaceutical preparations which comprisethe compounds of the formula I.

cGMP is an important intracellular messenger which triggers a multitudeof different effects via the modulation of cGMP-dependent proteinkinases, phosphodiesterases and ion channels. Examples are therelaxation of smooth muscles, the inhibition of thrombocyte activationand the inhibition of the proliferation of smooth-muscle cells and ofleukocyte adhesion. cGMP is produced by particulate and solubleguanylate cyclases “GC” as a response to a number of extra- andintracellular stimuli. In the case of the particulate guanylatecyclases, stimulation is essentially effected by peptidic messengers,such as the atrial natriuretic peptide or the cerebral natriureticpeptide. The soluble guanylate cyclases “sGC,” which are cytosolicheterodimeric heme proteins, in contrast, are essentially regulated by afamily of low-molecular-weight factors which are formed enzymatically.The most important stimulant is nitrogen monoxide “NO” or a closelyrelated species. The function of other factors such as carbon monoxideor the hydroxyl radical is still largely unclear. Binding of NO to theheme with formation of a penta-coordinate heme-nitrosyl complex is beingdiscussed as activation mechanism of the activation by NO. Theassociated release of the histidine which is bound in the basal state tothe iron converts the enzyme into the active conformation.

Active soluble guanylate cyclases are in each case composed of an α anda β subunit. Several subunit subtypes have been described which differfrom one another with respect to sequence, tissue-specific distributionand expression in different development stages. The subtypes α₁ and β₁are mainly expressed in brain and lung, while β₂ is found in particularin liver and kidney. The subtype α₂ was shown to be present in humanfetal brain. The subunits referred to as α₃ and β₃ were isolated fromhuman brain and are homologous to α₁ and β₁. More recent works indicatean α_(2i) subunit which contains an insert in the catalytic domain. Allsubunits show great homologies in the region of the catalytic domain.The enzymes presumably contain one heme per heterodimer, which is boundvia β₁-Cys-78 and/or β₁-His-105 and is part of the regulatory center.

Under pathologic conditions, the formation ofguanylate-cyclase-activating factors can be reduced, or theirdegradation may be promoted owing to the increased occurrence of freeradicals. The resulting reduced activation of the sGC leads, via aweakening of the respective cGMP-mediated cellular response, for exampleto an increase of the blood pressure, to platelet activation or toincreased cell-proliferation and cell adhesion. As a consequence,formation of endothelial dysfunction, atherosclerosis, hypertension,stable and unstable angina pectoris, thromboses, myocardial infarction,strokes or erectile dysfunction results. Pharmacological stimulation ofsGC offers a possibility to normalize cGMP production and thereforemakes possible the treatment and/or prevention of such disorders.

For the pharmacological stimulation of the sGC, use has hitherto almostexclusively been made of compounds whose activity is based on anintermediate NO release, for example organic nitrates. The drawback ofthis treatment is the development of tolerance and a reduction ofactivity, and the higher dosage which is required because of this.

Various sGC stimulators which do not act via NO release were describedby Veseley in a quite large number of applications. However, thecompounds, most of which are hormones, plant hormones, vitamins or, forexample, natural compounds such as lizard poisons predominantly onlyhave weak effects on the cGMP formation in cell lysates (D. L. Veseley,Eur. J. Clin. Invest. 15 (1985) 258; D. L. Veseley, Biochem. Biophys.Res. Comm. 88 (1979) 1244). A stimulation of heme-free guanylate cyclaseby protoporphyrin IX was demonstrated by Ignarro et al. (Adv. Pharmacol.26 (1994) 35). Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307)described an antihypertensive action of diphenyliodoniumhexafluorophosphate and attributed this to a stimulation of sGC.According to Yu et al. (Brit. J. Pharmacol. 114 (1995) 1587),isoliquiritigenin, which has a relaxing action on isolated rat aortas,also activates sGC. Ko et al. (Blood 84 (1994) 4226), Yu et al.(Biochem. J. 306 (1995) 787) and Teng et al. (Brit. J. Pharmacol. 116(1995) 1973) demonstrated a sGC-stimulating activity of1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated anantiproliferative and thrombocyte-inhibiting action. EP-A-667 345describes various indazoles as inhibitors of thrombocyte aggregation.

Surprisingly, it has not been reported until now that the pyrazolederivatives of the formula I effect guanylate cyclase activation and aretherefore suitable for the therapy and prophylaxis of disorders whichare associated with a low cGMP level.

Thus, the present invention relates to compounds of the formula I

in which

-   -   X is O, S, NH or N(CH₃);    -   R¹ and R^(1a) are identical or different, and are hydrogen,        halogen, OR⁶, NR⁷R⁸, CO—OR⁹, CO—R¹⁰, CO—NR¹¹R¹², CO—NR¹²—OR¹¹,        S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵, CN, NO₂, (C₁-C₁₀)-alkyl,        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, the radical Het or the radical        Het-(C₁-C₄)-alkyl,    -   where alkyl radicals, aryl radicals, arylalkyl radicals,        cycloalkyl radicals, cycloalkylalkyl radicals, radicals Het and        radicals Het-alkyl representing R¹ or R^(1a) may in each case be        unsubstituted or substituted by one or more substituents R⁵, and        where R¹ can be NO₂ only in the case when simultaneously R^(1a)        is hydrogen, the radicals R² and R³ together with the carbon        atoms which carry them form an unsubstituted benzene ring or a        benzene ring which is substituted by one or more substituents        R⁵, and the radical —(CH₂)_(n)—R⁴ is different from        unsubstituted phenyl;    -   R² and R³ are identical or different, and are hydrogen,        (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl,        (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, the        radical Het or the radical Het-(C₁-C₄)-alkyl, where alkyl        radicals, aryl radicals, arylalkyl radicals, cycloalkyl        radicals, cycloalkylalkyl radicals, radicals Het and radicals        Het-alkyl representing R² or R³ may in each case be        unsubstituted or substituted by one or more substituents R⁵,    -   or R² and R³ together with the carbon atoms which carry them        form a 5- to 7-membered carbocyclic ring which may contain one        or more double bonds and which may be unsubstituted or        substituted by one or more substituents R⁵;        -   R⁴ is hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,            (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,            (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, the radical Het or the            radical Het-(C₁-C₄)-alkyl, where alkyl radicals, aryl            radicals, arylalkyl radicals, cycloalkyl radicals,            cycloalkylalkyl radicals, radicals Het and radicals            Het-alkyl representing R⁴ may in each case be unsubstituted            or substituted by one or more substituents R⁵, and where, if            n=0, R⁴ may not be hydrogen;    -   n is 0, 1 or 2;    -   Het is a 5- to 7-membered, saturated or unsaturated heterocycle;    -   R⁵ is halogen, (C₁-C₅)-alkyl, OR⁶, NR⁷R⁸, CO—OR⁹, CO—R¹⁰,        CO—NR¹¹R¹², CO—NR¹²—OR¹¹, S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵, NO₂, CN        or CF₃, where radicals R⁵ that occur more than once are        identical or different;    -   R⁶, R⁷, R⁸, R¹¹ and R¹⁴ are identical or different, and are        hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, the radical Het, the radical        Het-(C₁-C₄)-alkyl, CO—R¹⁶ or S(O)₂—R¹⁷, where alkyl radicals,        aryl radicals, arylalkyl radicals, cycloalkyl radicals,        cycloalkylalkyl radicals, radicals Het and radicals Het-alkyl        representing R⁶, R⁷, R⁸, R¹¹ and R¹⁴ may in each case be        unsubstituted or substituted by one or more identical or        different substituents selected from the group consisting of        halogen, (C₁-C₅)-alkyl, OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²²,        CO—NR²³R²⁴, CO—NR²⁴—OR²³, S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷, NO₂, CN        and CF₃, and where radicals R⁶, R⁷, R⁸, R¹¹ and R¹⁴ that occur        more than once are identical or different;    -   R⁹, R¹⁰, R¹², R¹³ and R¹⁵ are identical or different, and are        hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, the radical Het or the radical        Het-(C₁-C₄)-alkyl, where alkyl radicals, aryl radicals,        arylalkyl radicals, cycloalkyl radicals, cycloalkylalkyl        radicals, radicals Het and radicals Het-alkyl representing R⁹,        R¹⁰, R¹², R¹³ and R¹⁵ may in each case be unsubstituted or        substituted by one or more identical or different substituents        selected from the group consisting of halogen, (C₁-C₅)-alkyl,        OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴, CO—NR²⁴—OR²³,        S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷, NO₂, CN and CF₃, and where radicals        R⁹, R¹⁰, R¹², R¹³ and R¹⁵ that occur more than once are        identical or different;    -   or the two radicals R⁷ and R⁸, the two radicals R¹¹ and R¹² and        the two radicals R¹⁴ and R¹⁵, in each case together with the        nitrogen atom which carries the two radicals, form a 5- to        7-membered, saturated or unsaturated heterocyclic ring which may        contain an additional ring heteroatom selected from the group        consisting of nitrogen, oxygen and sulfur and which may be        substituted by one or more identical or different substituents        selected from the group consisting of (C₁-C₄)-alkyl and halogen;    -   R¹⁶ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, the radical Het or the radical        Het-(C₁-C₄)-alkyl;    -   R¹⁷ is (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, the radical Het or the radical        Het-(C₁-C₄)-alkyl;    -   R¹⁸, R¹⁹, R²⁰, R²³ and R²⁶ are identical or different, and are        hydrogen, (C₁-C₁₀)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, the radical Het, the radical        Het-(C₁-C₄)-alkyl, CO—R¹⁶ or S(O)₂—R¹⁷, where radicals R¹⁸, R¹⁹,        R²⁰, R²³ and R²⁶ that occur more than once are identical or        different;    -   R²¹, R²², R²⁴, R²⁵ and R²⁷ are identical or different, and are        hydrogen, (C₁-C₁₀)-alkyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, the radical Het or the radical        Het-(C₁-C₄)-alkyl, where radicals R²¹, R²², R²⁴, R²⁵ and R²⁷        that occur more than once are identical or different;    -   or the two radicals R¹⁹ and R²⁰, the two radicals R²³ and R²⁴        and the two radicals R²⁶ and R²⁷, in each case together with the        nitrogen atom which carries the two radicals, form a 5- to        7-membered, saturated or unsaturated heterocyclic ring which may        contain an additional ring heteroatom selected from the group        consisting of nitrogen, oxygen and sulfur and which may be        substituted by one or more identical or different substituents        selected from the group consisting of (C₁-C₄)-alkyl and halogen;    -   m is 0, 1 or 2;    -   in all their stereoisomer forms and mixtures thereof in all        ratios, and their physiologically acceptable salts;    -   except for compounds of the formula I where the following        radicals simultaneously have the following meanings: R¹ is a        radical in the 5-position of the furan ring, thiophene ring or        pyrrole ring selected from the group consisting of hydrogen,        (C₁-C₃)-alkyl, COOH, CO—O—(C₁-C₃)-alkyl, CH₂—OH,        CH₂—O—(C₁-C₃)-alkyl and halogen; R^(1a) is hydrogen; R² and R³        together with the carbon atoms which carry them are a benzene        ring which is unsubstituted or monosubstituted by a radical        selected from the group consisting of (C₁-C₃)-alkyl, halogen,        hydroxyl and (C₁-C₃)-alkoxy; n is the number 1; R⁴ is        unsubstituted phenyl or phenyl which is monosubstituted by a        radical selected from the group consisting of (C₁-C₃)-alkyl,        halogen, hydroxyl and (C₁-C₃)-alkoxy;    -   and except for the compound of the formula I where the radicals        simultaneously have the following meanings: X is S; R¹ is a        chlorine atom which is attached to the 5-position of the        thiophene ring; R^(1a) is hydrogen; R² is methyl; R³ is        hydrogen; n is 0; R⁴ is the radical (CH₃)₂N—CO—CH(CH₃)—.

Alkyl radicals may be straight-chain or branched. This also applies whenthey are substituted, for example by an aryl radical in an arylalkylgroup or by the radical Het in the group Het-alkyl or when they are partof other groups, for example in alkoxy groups, alkoxycarbonyl groups orN-alkyl-substituted carbamoyl groups. Examples of alkyl groups aremethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl,n-heptyl, n-octyl, n-nonyl and n-decyl. The term alkyl here alsoincludes unsaturated alkyl radicals, in particular alkyl radicals whichcontain one or two double bonds or one or two triple bonds or a doublebond and a triple bond. Examples of such radicals are the vinyl radical,the 2-propenyl radical (allyl radical), the 2-butenyl radical, the3-methyl-2-butenyl radical, the ethinyl radical, the 2-propinyl radical(propargyl radical) or the 3-butinyl radical.

Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl radicals may also besubstituted by alkyl groups, for example by one or more methyl groups.

Examples of (C₆-C₁₄)-aryl radicals are phenyl, naphthyl, anthracenyl,biphenylyl or fluorenyl, where the polynuclear radicals may be linkedvia all positions. Thus, naphthyl radicals, for example, may be presentas 1-naphthyl radicals or 2-naphthyl radicals. A preferred aryl radicalis the phenyl radical. Aryl radicals may be unsubstituted or mono- orpolysubstituted, for example di- or trisubstituted, and the substituentsmay be in any position. Monosubstituted phenyl radicals may besubstituted in the 2-position, the 3-position or the 4-position,disubstituted phenyl radicals in the 2,3-position, the 2,4-position, the2,5-position, the 2,6-position, the 3,4-position or the 3,5-position. Intrisubstituted phenyl radicals, the substituents may be, for example, in2,3,4-position, 2,3,5-position, 2,3,6-position or 3,4,5-position. Theseillustrations for aryl radicals also apply to those aryl radicals whichare part of arylalkyl radicals, for example of benzyl radicals,1-phenylethyl radicals, 2-phenylethyl radicals or naphthylmethylradicals. Preferred arylalkyl radicals are phenylethyl radicals and inparticular the benzyl radical. The 5- to 7-membered, saturated orunsaturated, heterocycles representing the group

Het preferably contain one, two, three or four ring heteroatoms selectedfrom the group consisting of nitrogen, oxygen and sulfur. Particularlypreferably, they contain one, two or three heteroatoms from this group.Unsaturated heterocycles may contain one, two or three double bonds inthe ring. The 5-membered ring and 6-membered ring heterocycles may inparticular also be aromatic, i.e., Het in the compounds of the formula Imay also be 5- or 6-membered hetaryl which may be unsubstituted orsubstituted. Examples of heterocyclic 5-membered ring, 6-membered ringand 7-membered ring systems from which the radicals in question may bederived are pyrrole, furan, thiophene, imidazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole, 1,2-oxazole,1,3thiazole, 1,2-thiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, pyran, thiopyran, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine,1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepine,1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxepine or1,3-thiazepine, all in each case in saturated form (perhydro form) or inpartially unsaturated form (dihydro form and tetrahydro form) or inmaximally unsaturated form (aromatic form in the case of the 5-memberedrings and 6-membered rings), insofar as the forms in question are knownand stable. Thus, the heterocycles which are suitable also include, forexample, the saturated heterocycles pyrrolidine, piperidine, piperazine,morpholine and thiomorpholine.

The heterocyclic radical may be attached via any carbon atom, i.e., forexample, in the case of radicals which are derived from the furansystem, the thiophene system or the pyrrole system, it may be attachedin the 2-position or the 3-position, in the case of radicals derivedfrom the imidazole system or from the 1,3-thiazole system, it may beattached in the 2-position, the 4-position or the 5-position, or in thecase of radicals which are derived from the pyridine system, it may beattached in the 2-position, the 3-position or the 4-position. Nitrogenheterocycles, which may carry a substituent at a ring nitrogen atom, mayalso be attached via a ring nitrogen atom if the heterocyclic radical inquestion is attached to a carbon atom. The heterocycles may be mono- orpolysubstituted, for example disubstituted, trisubstituted ortetrasubstituted, and may be substituted in any positions. Substituentson a heterocycle may also form a ring, i.e. condensed heterocycles maybe present, for example cyclopenta-condensed, cyclohexa-condensed orbenzo-condensed heterocycles. Suitable substituents at a nitrogen atomof a heterocycle are in particular, for example, (C₁-C₅)-alkyl radicalsor the radicals CO—R¹⁶ or SO₂—R¹⁷, but also, for example, aryl radicalsor arylalkyl radicals. Nitrogen heterocycles may also be present asN-oxides.

Halogen is, unless stated otherwise, fluorine, chlorine, bromine oriodine, preferably fluorine or chlorine.

If alkyl radicals, aryl radicals, arylalkyl radicals, cycloalkylradicals, cycloalkylalkyl radicals or the radicals Het or Het-alkyl aresubstituted by radicals R⁵, they may be substituted by one, two, three,four or more identical or different radicals R⁵. Such substitutedradicals preferably contain one, two or three identical or differentradicals R⁵. In the case of the arylalkyl radicals, cycloalkylalkylradicals and the radicals Het-alkyl, the radicals R⁵ may in each case bein the alkyl moiety and/or in the aryl moiety and/or cycloalkyl moietyand/or the radical Het. If R² and R³ together with the carbon atomswhich carry them form a carbocyclic ring which is substituted by one ormore radicals R⁵, this ring is preferably substituted by one, two, threeor four identical or different radicals R⁵, particularly preferably byone or two radicals. The radicals R⁵ may be in any positions.

The two substituents R¹ and R^(1a) may be in any positions of theheterocycle, i.e. in the positions 3, 4 and 5 of the furan ring,thiophene ring or pyrrole ring.

If R² and R³ together with the carbon atoms which carry them form a 5-to 7-membered carbocyclic ring, condensed pyrazoles are present. In thecase of a fused-on 5-membered ring, i.e. in the case ofcyclopenta-condensed pyrazoles, the carbocyclic ring may, in addition tothe double bond that it shares with the pyrazole ring, contain a furtherdouble bond in the ring or no further double bonds in the ring. In thecase of a fused-on 6-membered ring (i.e. in the case ofcyclohexa-condensed pyrazoles) or in the case of a fused-on 7-memberedring (i.e. in the case of a cyclohepta-condensed pyrazole) thecarbocyclic ring may, in addition to the double bond which it shareswith the pyrazole ring, contain a further double bond in the ring or twofurther double bonds in the ring or no further double bonds in the ring.The double bonds in the carbocyclic ring may be in any positions, butcumulated double bond systems may not be present. If R² and R³ togetherwith the carbon atoms which carry them form a 6-membered carbocyclehaving a total of three double bonds, a benzene ring is fused to thepyrazole ring, the compounds of the formula I are in this casebenzo-pyrazoles (formula Ia) which are also called indazoles (thecompounds according to the invention are 1H-indazoles just as thenon-benzo-fused pyrazoles are 1H-pyrazoles). Examples of such compoundsof the formula I in which R² and R³ together with the carbon atoms whichcarry them form a carbocyclic ring are the compounds of the formulae Ia,Ib, Ic and Id, in which X, R¹, R^(1a), R⁴, R⁵ and n are as defined aboveand y, in accordance with the statements above, is 0 or an integer,preferably 0, 1, 2, 3 or 4, particularly preferably 0, 1 or 2. Theradicals R⁵, which may be identical or different, may be in anypositions in the carbocycle.

The heterocyclic rings which may be formed by the two radicals R⁷ andR⁸, the two radicals R¹¹ and R¹², the two radicals R¹⁴ and R¹⁵, the tworadicals R¹⁹ and R²⁰, the two radicals R²³ and R²⁴ and the two radicalsR²⁶ and R²⁷, in each case together with the nitrogen atom which carriesthe two radicals, may be saturated or partially unsaturated or maximallyunsaturated. They are preferably saturated. Examples of such rings whichare attached via a ring nitrogen atom to a carbonyl group or a sulfonylgroup are in particular pyrroline, pyrrolidine, piperidine, piperazine,morpholine and thiomorpholine. These rings may be substituted at carbonatoms and, in the case of piperazine, also at the nitrogen atom in the4-position, and may also be, in the case of the thiomorpholine, beoxidized at the sulfur to the sulfoxide or to the sulfone.

If n in the formula I is the number 0, the radical R⁴ is attacheddirectly to the pyrazole nitrogen atom.

If they are appropriately substituted, the compounds of the formula Imay be present in stereoisomeric forms. If the compounds of the formulaI contain one or more centers of symmetry, these are identical ordifferent from each other and have the S configuration or the Rconfiguration. The invention includes all possible stereoisomers, forexample enantiomers and diastereomers, and mixtures of two or morestereoisomeric forms, for example mixtures of enantiomers and/ordiastereomers, in all ratios. Thus, the invention provides enantiomersin enantiomerically pure form, both as levorotatory and asdextrorotatory antipodes, in the form of racemates and in the form ofmixtures of the two enantiomers in all ratios. In the case of acis/trans isomerism, the invention provides both the cis form and thetrans form and mixtures of these forms. The preparation of individualstereoisomers can be carried out, if desired, by separation of a mixtureby customary methods, for example by chromatography or crystallization,by the use of stereochemically uniform starting materials for thesynthesis or by stereoselective synthesis. The separation of a mixtureof stereoisomers can be carried out at the stage of the compounds of theformula I or during the synthesis.

If mobile hydrogen atoms are present, the present invention alsoincludes all tautomeric forms of the compounds of the formula I, forexample lactam/lactim tautomers.

If the compounds of the formula I contain one or more acidic or basicgroups, the invention also provides the corresponding physiologically ortoxicologically tolerable salts, in particular the pharmaceuticallyacceptable salts. Thus, the compounds of the formula I which contain oneor more acidic groups, for example COOH groups or N-acylsulfonamidogroups, may be present on these groups and may be used according to theinvention, for example as alkali metal salts, alkaline earth metal saltsor as ammonium salts. Examples of such salts are sodium salts, potassiumsalts, calcium salts, magnesium salts or salts with ammonia or organicamines, such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of the formula I which contain one or morebasic groups, i.e., groups which can be protonated, can be present andcan be used according to the invention in the form of their acidaddition salts with inorganic or organic acids which, for example assalts with hydrogen chloride, hydrogen bromide, phosphoric acid,sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonicacid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaricacid, lactic acid, salicylic acid, benzoic acid, formic acid, propionicacid, pivalic acid, diethylacetic acid, malonic acid, succinic acid,pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid,phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid,citric acid, adipic acid, etc.

If the compounds of the formula I simultaneously contain acidic andbasic groups in the molecule, the invention also includes, in additionto the salt forms mentioned, inner salts, so-called betaines. Salts canbe obtained from the compounds of the formula I by customary methodswhich are known to the person skilled in the art, for example bycombination with an organic or inorganic acid or base in a solvent ordispersant, or else by anion exchange or cation exchange from othersalts. The present invention also includes all salts of the compounds ofthe formula I which, owing to low physiological compatibility, are notdirectly suitable for use in pharmaceuticals but which can be used, forexample, as intermediates for chemical reactions or for the preparationof physiologically acceptable salts.

The present invention furthermore includes all solvates of compounds ofthe formula I, for example hydrates or adducts with alcohols, and alsoderivatives of the compounds of the formula I, for example esters,prodrugs and metabolites, which act like the compounds of the formula I.

In the formula I, X is preferably O or S, and most preferably O.

R¹ is preferably (C₁-C₁₀)-alkyl which is substituted by hydroxyl, inparticular CH₂OH or CH(OH)—((C₁-C₅)-alkyl), or is CO—OR⁹ or CO—NR¹¹R¹².Particularly preferably, the radical R¹ is in the 5-position of theheterocycle. R^(1a) is preferably hydrogen.

R² and R³ preferably form, together with the carbon atoms which carrythem, a benzene ring which may be unsubstituted or substituted by one ormore identical or different substituents R⁵ (the compounds according tothe invention in which R² and R³ have these preferred meanings are thebenzo-condensed pyrazoles of the formula Ia).

n is preferably 0 or 1.

R⁴ is preferably (C₆-C₁₄)-aryl, in particular phenyl, or 5- or6-membered heteroaryl, it being possible for these radicals to besubstituted or unsubstituted.

Radicals R⁵ which are present in the radicals R² and R³ are preferablyhalogen, (C₁-C₃)-alkyl, CF₃, (C₁-C₃)-alkyl-O or S(O)₂—NR¹⁴R¹⁵,particularly preferably CF₃, radicals R⁵ which are present in theradical R⁴ are preferably halogen, (C₁-C₃)-alkyl, or CF₃.

R⁶ is preferably hydrogen or (C₁-C₃)-alkyl.

R⁷ is preferably hydrogen, (C₁-C₃)-alkyl, CO—R¹⁶ or S(O)₂—R¹⁷.

R⁸ is preferably hydrogen.

R⁹ is preferably CH₂CH₂—OH or CH₂CH₂—NR¹⁹R²⁰.

R¹⁰ is preferably (C₁-C₃)-alkyl or unsubstituted or substituted phenyl.

R¹¹ is preferably hydrogen.

R¹² is preferably unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl which issubstituted by a radical selected from the group consisting of OR¹⁸,NR¹⁹R²⁰ and CO—NR²³R²⁴, 5- or 6-membered heteroaryl, unsubstitutedphenyl or phenyl which is substituted by one, two or three identical ordifferent radicals selected from the group consisting of halogen,(C₁-C₅)-alkyl, OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴, S(O)_(m)—R²⁵,S(O)₂—NR²⁶R²⁷, NO₂, CN and CF₃.

R¹³ is preferably (C₁-C₃)-alkyl, unsubstituted phenyl, phenyl which issubstituted by one, two or three identical or different radicalsselected from the group consisting of halogen, (C₁-C₃)-alkyl, OR¹⁸,NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴, S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷, NO₂,CN and CF₃, or is 5- or 6-membered heteroaryl.

R¹⁴ is preferably (C₁-C₃)-alkyl, 5- or 6-membered heteroaryl, CO—R¹⁶,unsubstituted phenyl or phenyl which is substituted by one, two or threeidentical or different radicals selected from the group consisting ofhalogen, (C₁-C₅)-alkyl, OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴,S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷, NO₂, CN and CF₃.

R¹⁵ is preferably hydrogen.

It is also preferred when the radicals R¹⁴ and R¹⁵ together with thenitrogen atom which carries the two radicals form a 5- to 7-memberedsaturated ring which, particularly preferably, contains an oxygen atom,a sulfur atom or a nitrogen atom which is substituted by a methyl groupas additional ring heteroatom.

R¹⁶ is preferably (C₁-C₃)-alkyl.

R¹⁷ is preferably (C₁-C₃)-alkyl.

R¹⁸ is preferably hydrogen or (C₁-C₃)-alkyl.

R¹⁹ is preferably hydrogen.

R²⁰ is preferably CO—(C₁-C₃)-alkyl or CO—(C₆-C₁₄)-aryl,S(O)₂—(C₁-C₃)-alkyl or S(O)₂—(C₆-C₁₄)-aryl.

R²¹, R²², R²⁴ and R²⁵ are preferably (C₁-C₃)-alkyl.

R²³ is preferably hydrogen or (C₁-C₃)-alkyl.

R²⁶ is preferably (C₁-C₃)-alkyl or CO—R¹⁶.

R²⁷ is preferably hydrogen.

It is also preferred when R²⁶ and R²⁷ together with the nitrogen atomwhich carries the two radicals form a 5- to 7-membered saturated ringwhich, particularly preferably, contains an oxygen atom, a sulfur atomor a nitrogen atom which is substituted by a methyl group as additionalring heteroatom.

A 5- or 6-membered heteroaryl radical is preferably the radical of anaromatic heterocycle having one, two, three or four heteroatoms selectedfrom the group consisting of nitrogen, oxygen and sulfur, particularlypreferably having one or two heteroatoms or the tetrazolyl radical. Veryparticularly preferably, a 5- or 6-membered heteroaryl radical is theradical of one of the aromatic heterocycles furan, thiophene,1,3-thiazole, 1,3-oxazole, 1,2-oxazole, tetrazole, pyridine andpyrimidine, and additionally, preferably, of 1,3-thiazole or oftetrazole. These radicals are attached via a carbon atom and can beunsubstituted or substituted as mentioned above.

Preferred compounds of the formula I are those in which one or more ofthe radicals contained therein have preferred meanings, all combinationsof preferred substituent definitions being included. The presentinvention also includes all stereoisomeric forms and mixtures thereof inall ratios, and the physiologically acceptable salts, of all preferredcompounds of the formula I.

The compounds of the formula I can be prepared by various processes,which are described hereinbelow and which also form part of the subjectmatter of the present invention. Compounds of the formula I in which theradicals R² and R³ together with the carbon atoms which carry them donot form a benzene ring, i.e., in which the radicals R² and R³ arehydrogen or an unsubstituted or substituted alkyl radical, aryl radical,arylalkyl radical, cycloalkyl radical, cycloalkylalkyl radical, theradical Het or the radical Het-alkyl or in which R² and R³ together withthe carbon atoms which carry them form an unsubstituted or substitutednonaromatic carbocyclic ring can be prepared by reacting 1,3-dicarbonylcompounds of the formula II with hydrazines of the formula III or saltsthereof to give compounds of the formula Ie′. In the formulae II and IIIand in the formula Ie′, the radicals X, R^(1′), R^(1a′), R^(2′), R^(3′)and R^(4′) and the number n may have the abovementioned meanings of X,R¹, R^(1a), R², R³, R⁴ and n, but the radicals R^(2′) and R^(3′)together with the carbon atoms which carry them may not form an aromaticring, and additionally functional groups in the radicals R^(1′),R^(1a′), R^(2′), R^(3′) and R^(4′) may be present in protected form orin the form of precursors.

Suitable protective groups or favorable precursors for functional groupsin these radicals are known to the person skilled in the art. Forexample, a carbonyl group in these radicals may initially be present inprotected form, for example in the form of an acetal or ketal, or anamino group may be present in acylated form, or a hydrogen atom may bepresent as a precursor for a group which is introduced in anelectrophilic substitution reaction. If appropriate, compounds of theformula Ie according to the invention can then be obtained fromcompounds of the formula Ie′ by converting thegroups which are presentin protected form or in the form of precursors in a subsequent reactionstep into the desired functional groups mentioned in the abovedefinitions of R¹, R^(1a), R², R³ and R⁴.

Thus, in the resulting compounds of the formula Ie, X, R¹, R^(1a), R²,R³, R⁴ and n have the meanings given above for the formula I, but R² andR³ together with the carbon atoms which carry them may not form abenzene ring, i.e., R² and R³ are hydrogen or an unsubstituted orsubstituted alkyl radical, aryl radical, arylalkyl radical, cycloalkylradical, cycloalkylalkyl radical, the radical Het or the radicalHet-alkyl, or R² and R³ together with the carbon atoms which carry themform an unsubstituted or substituted non-aromatic 5- to 7-memberedcarbocyclic ring.

Reactions of compounds of the formula II with the hydrazines of theformula III or salts thereof are preferably carried out in a solvent ordispersant. Suitable solvents are for example, water, alcohols, such asmethanol, ethanol, n-propanol, isopropanol or butanols, ethers, such asdiethyl ether, dipropyl ether, dibutyl ether, methyl-tert-butyl ether,tetrahydrofuran or dioxane, monoethers and diethers of ethylene glycoland of di- and triethylene glycol, such as ethylene glycol monomethylether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether,ethylene glycol monobutyl ether, diethylene glycol monomethyl ether ordiethylene glycol dimethyl ether, esters, such as ethyl acetate or butylacetate, amides, such as dimethylformamide, dimethylacetamide,N-methylpyrrolidone or hexamethylphosphoric triamide, nitriles, such asacetonitrile, acids such as acetic acid, sulfoxides and sulfones, suchas dimethyl sulfoxide or sulfolane, hydrocarbons and chlorinatedhydrocarbons, such as petroleum fractions, benzene, toluene, xylene,chlorobenzene, dichlorobenzene, methylene chloride or chloroform. It isalso possible to employ mixtures of two or more solvents, for examplemixtures of water and alcohols, mixtures of water and acids or mixturesof alcohols and acids. Preferred solvents are alcohols such as methanoland ethanol.

The reaction is generally carried out at temperatures from 0° C. to 150°C., preferably at temperatures from 20° C. to 130° C. Particularpreference is given to carrying out the reaction under reflux at theboiling point of the solvent or solvent mixture used, for example at theboiling point of methanol or ethanol. The reaction time is determined bythe individual case and depends, for example, on the reactivity of thereactants and the reaction conditions. The reaction is generallycomplete after 1 to 10 hours if the reaction is carried out in methanolor ethanol at boiling point. The work-up of the reaction mixture can becarried out by standard methods, and the product can, if desired, bepurified by customary purification methods, for example byrecrystallization or chromatography.

If free hydrazines of the formula III are employed, it is in many casesparticularly advantageous to carry out the reaction with the dicarbonylcompounds of the formula II under acid catalysis. Suitable catalystsare, for example, organic carboxylic acids and sulfonic acids, such asacetic acid, trifluoroacetic acid, methanesulfonic acid orp-toluenesulfonic acid, inorganic acids, such as hydrogen chloride,sulfuric acid or phosphoric acid, acidic salts, such as ammonium saltsor hydrogen phosphates, or acidic ion exchangers. It may also befavorable to set a certain pH, or to operate in the presence of a buffersystem. It is also possible to liberate the dicarbonyl compound of theformula II from a precursor, for example an acetal or ketal, using anacid catalyst, i.e., the dicarbonyl compound can be employed in the formof such a precursor. Preference is given to carrying out the reaction ofcompounds of the formula II with free hydrazines of the formula III inthe presence of acetic acid.

The type and the amount of an added acid catalyst is determined by theindividual case and depends, for example, on the reactivity of thereactants, the solvent or the intended temperature. If, for example, anacid such as acetic acid is used, this can act both as solvent and ascatalyst, depending on the amount employed. If an acid addition salt ofa hydrazine, for example an R^(4′)—(CH₂)_(n)-substituted hydraziniumchloride or hydrazinium sulfate, is employed instead of a freehydrazine, an acidic compound, which may act catalytically, is alreadyintroduced into the reaction mixture in this manner. If a hydraziniumsalt is used, it is in many cases advantageous to buffer a part of theacid which has been introduced by addition of a certain amount of abase, for example by addition of sodium acetate or another bufferingsubstance to the reaction mixture, to set a favorable pH.

The ratio at which the compounds of the formulae II and III areadvantageously employed for the reaction depends on the individual case.The ratio may be approximately 1:1, but it is also possible to employ areactant in a relatively low amount or a relatively large excess. If,for example, a reactant is prepared with great expense in a multi-stepsynthesis and the other reactant is easily obtained, it may befavorable, in order to make as much use as possible of the former, toemploy the latter in excess, for example in 1.1- to 5-times the molaramount of the former.

In the reaction of the compounds of the formulae II and III to give thecompound of the formula Ie′, it may be possible that initially, asintermediate, the hydrazone of the formula IV is formed in which theradicals and n have the meanings given above for the formulae II and IIIand which may be isolable, depending on the reaction conditions used.Depending on the individual case, it may be advantageous, by the choiceof the reaction conditions such as solvent, temperature and catalyst, tocarry out the reaction in such a manner that it initially only proceedsto the hydrazone of the formula IV, which is then cyclized in a separatestep to give the pyrazole of the formula Ie′. However, it may also beadvantageous to carry out the reaction in such a manner that thepyrazole is formed directly. If the reaction is carried out in twosteps, the hydrazone of the formula IV may, for cyclization, be isolatedin substance, or the reaction mixture of the hydrazone preparation maybe used and the cyclization may be effected for example by raising thetemperature and/or by addition of a catalyst.

Depending on the reaction conditions and the reactivities of thereactants, the NH₂ group of the hydrazine of the formula III may,instead of with the carbonyl group which is adjacent to the heterocyclein the formula II, also react with the carbonyl group which is adjacentto the radical R^(3′). In this case, the reaction may also lead to theunwanted isomeric pyrazole of the formula VI, it being again possiblethat initially a hydrazone of the formula V is formed as intermediatewhich, if appropriate, may be isolated. In the formulae V and VI, theradicals and n have the meanings given above for the formulae II andIII. If the reaction of the compounds of the formulae II and III yieldsmixtures of the isomeric pyrazoles Ie′ and VI, these can be separatedinto the components by customary methods, for example byrecrystallization or, in particular, by chromatography. A separation ofan isomer mixture can also be carried out at the stage of thehydrazones.

Compounds of the formula I according to the invention in which theradicals R² and R³ together with the carbon atoms which carry them forma benzene ring, i.e., compounds of the formula Ia, can be prepared byreacting compounds of the formula VII with hydrazines of the formula IIIor salts thereof. In the formulae VII, VIII and Ia′, the radicals X,R^(1′), R^(1a′), R^(4′), R^(5′) and the number n may have theabovementioned meanings of X, R¹, R^(1a), R⁴, R⁵ and n, but it is alsopossible that functional groups in these radicals are present inprotected form or in the form of precursors. In the formulae Ia′, VIIand VIII, y has the abovementioned meanings, i.e. y may here be 0, 1, 2,3 or 4. Z¹ in the formulae VII and VIII is a leaving group, for examplehalogen, or another suitable group, such as thetrifluoromethanesulfonyloxy radical. Z¹ is preferably fluorine. Ifappropriate, compounds of the formula Ia according to the invention maythen be obtained from the compounds of the formula Ia′ by converting, ina subsequent reaction step, the groups which are present in protectedform or in the form of precursors into the desired functional groupsmentioned in the above definitions of R¹, R^(1a), R⁴ and R⁵.

As in the reaction of compounds of the formulae II and III, in thereaction of compounds of the formulae VII and III a hydrazone maylikewise be initially formed as intermediate, i.e., a compound of theformula VIII which may be isolable, depending on the reactivity of thestarting materials used and the reaction conditions. Depending on theindividual case, it may be advantageous to carry out the reaction of thecompounds of the formulae III and VII by the choice of the reactionconditions such as solvents, temperature and catalyst in such a mannerthat it initially only leads to the hydrazone of the formulae VIII, andto cyclize this in a separate step to the indazole of the formula Ia′;however, it may also be favorable to carry out the reaction in such amanner that the indazole is formed directly.

In other cases, it may be suitable, owing to the reactivities of thestarting materials, to carry out the reaction in two steps and to changethe reaction conditions in the second step, the cyclization of thehydrazone of the formula VIII to the indazole of the formula Ia′. Thus,for example, if the group Z¹ in the compound of the formula VII or theformula VIII is not activated by substituents on the benzene ring, it isgenerally advantageous to condense initially the compounds of theformulae VII and III in the presence of an acid catalyst to give thehydrazone of the formula VIII, and to carry out the cyclization in asecond step by operating in the presence of a base which increases thenucleophilicity of the β-nitrogen atom in the hydrazone grouping. If thereaction is carried out in two steps, the hydrazone of the formula VIIImay be isolated in substance for the cyclization, or the reactionmixture of the hydrazone preparation may be employed for the cyclizationwithout isolation of the hydrazone.

The above explanations for the reaction of the compounds of the formulaeII and III with respect to solvents, reaction temperatures, catalysts,ratios, etc., apply correspondingly to the reaction of the compounds ofthe formulae VII and III. The reactions of compounds of the formula VIIwith the hydrazines of the formula III or salts thereof are likewisepreferably carried out in a solvent or dispersant. Here, too, suitablesolvents are, for example, water, alcohols, ethers, monoethers anddiethers of ethylene glycol and of di- and triethylene glycol, esters,amides, nitriles, acids, sulfoxides and sulfones, hydrocarbons andchlorinated hydrocarbons. Examples of these solvents are given above. Itis also possible to employ mixtures of two or more solvents. Here, too,preferred solvents are alcohols such as methanol and ethanol. Here, too,the reaction is generally carried out at temperatures from 0° C. to 150°C., preferably at temperatures from 20° C. to 130° C. The reaction isparticularly preferably carried out under reflux at the boiling point ofthe solvent used, for example at the boiling point of methanol orethanol.

If free hydrazines of the formula III are employed, it is in many casesparticularly advantageous to carry out the reaction with the compoundsof the formula VII under acidic catalysis. Once more, the aboveexplanations apply here, too. Here, too, preference is given to carryingout the reaction of compounds of the formula VII with free hydrazines ofthe formula III in the presence of acetic acid. If an acid addition saltof a hydrazine is employed instead of a free hydrazine, it is again inmany cases advantageous to buffer part of the acid that is introduced byaddition of a certain amount of a base, for example by addition ofsodium acetate, to set a favorable pH.

As already mentioned, the reaction of the compounds of the formulae VIIand III can be interrupted at the stage of the hydrazone of the formulaVIII. The cyclization of the hydrazone in a second step to give theindazole of the formula Ia′, which constitutes a nucleophilicsubstitution of the group Z¹ on the aromatic by the β-nitrogen atom ofthe hydrazono group, can be carried out, depending on the reactivitiesgiven in the individual case, for example by heating in a solvent ordispersant. In many cases, addition of a base is advantageous. If thecyclization in the preparation of compounds of the formula Ia′ iscarried out in a separate step, this step is preferably carried out inthe presence of a base. Suitable bases are, for example, hydroxides,carbonates, bicarbonates, hydrides, amides, alkoxides or organometalliccompounds of alkali metals such as lithium, sodium, potassium or cesiumor alkaline earth metals such as magnesium or calcium. Preferred basesare alkali metal alkoxides of (C₁-C₄)-alkanols such as sodium methoxideand potassium methoxide, sodium ethoxide and potassium ethoxide orsodium tert-butoxide and potassium tert-butoxide. It is also possible toemploy mixtures of two or more bases. The base is preferably employed inan equimolar amount or in excess, usually in 1 to 3 times the molaramount of the compound of formula VIII.

Suitable solvents or dispersants for a cyclization of a hydrazone of theformula VIII to the indazole in a separate step are, for example, water,alcohols, ethers, monoethers and diethers of ethylene glycol and of di-and triethylene glycol, esters, amides, nitriles, sulfoxides, sulfones,hydrocarbons and chlorinated hydrocarbons. Examples of these solventsare given above. It is also possible to employ mixtures of two or moresolvents. Preferred solvents for a cyclization in the presence of a baseare aprotic solvents, in particular dipolar aprotic solvents, such asdimethylformamide, dimethylacetamide, hexamethylphosphoric triamide,N-methylpyrrolidone or dimethyl sulfoxide.

A cyclization of the hydrazone of the formula VIII in a separate step isgenerally carried out at temperatures from 0° C. to 150° C., preferablyat temperatures from 20° C. to 130° C. Once more, particular preferenceis given to carrying out the cyclization under reflux at the boilingpoint of the solvent or solvent mixture used. Work-up can be carried outby standard methods.

A further process for preparing compounds of the formula Ia or Ia′ is,in addition to the reaction of compounds of the formula VII withR^(4′)—(CH₂)_(n)-substituted hydrazines of the formula III, the reactionof compounds of the formula VII with acylhydrazines of the formula IX.In the formula IX, R may, for example, be an alkyl radical, for examplea (C₁-C₄)-alkyl radical, such as the methyl radical or the tert-butylradical, or an aryl radical, for example a phenyl radical, which may beunsubstituted or substituted. An example of a suitable compound of theformula IX is benzhydrazide.

The reaction of the compounds of the formulae VII and IX can be carriedout under the same conditions as mentioned above for the reaction of thecompounds of the formulae VII and III. All of the above explanationsapply here in a corresponding manner. The reaction of the compounds ofthe formulae VII and IX, which again can be carried out in one step orin two steps, initially leads to the acylhydrazones or acylindazoleswhich correspond to the formulae VIII or Ia′ and contain, instead of thegroup R^(4′)—(CH₂)_(n), the group R—CO. After removal of the acyl group,these compounds give the indazoles of the formula X, in which X, R^(1′),R^(1a′), R^(5′) and y have the meanings given above for the formulaeIa′, VII and VIII.

For the removal of the acyl group, the acyl compounds may initially beisolated, but the removal can also be carried out in situ without theirisolation. The acyl group can be removed, for example, in a customarymanner by hydrolysis under acidic or basic conditions, for example usinghydrochloric acid, sulfuric acid, phosphoric acid, lithium hydroxide,sodium hydroxide, sodium carbonate or potassium hydroxide. It can becarried out in water or in a water-containing organic solvent ordispersant. The reaction temperature and reaction time depend on theindividual case, in general, the reaction is carried out from about roomtemperature to about 100° C. The indazoles of the formula X which areunsubstituted in the 1-position can be isolated by the customary methodsor else be employed directly in a subsequent reaction.

The indazoles of the formula X can then be converted into the1-substituted indazoles of the formula Ia′ by reaction with alkylatingagents of the formula XI. In the formula XI, R^(4′) and n are as definedabove, Z² is a leaving group, for example chlorine, bromine, iodine or asulfonyloxy radical, such as methanesulfonyloxy,trifluoromethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy.In general, the alkylating agent of the formula XI/is employed inequimolar amounts or in excess, for example in 1 to 3 times the molaramount of the compound of formula X.

The alkylation of the compounds of the formula X can be carried outunder the customary alkylation conditions. It is preferably carried outin a solvent or dispersant, for example in water, an alcohol, an ether,a monoether or diether of ethylene glycol or di- and triethylene glycol,a ketone, such as acetone or methyl ethyl ketone, an ester, an amide, anitrile, a sulfoxide or sulfone, a hydrocarbon or a chlorinatedhydrocarbon. The examples given above for these solvents also applyhere. It is also possible to employ mixtures of two or more solvents,for example mixtures of an organic solvent with water. The alkylation ispreferably carried out in water or in a dipolar aprotic solvent, forexample dimethylformamide. The alkylation is generally carried out attemperatures from about 0° C. to about 150° C., preferably attemperatures from about 20° C. to about 130° C. The alkylation isparticularly preferably carried out under reflux at the boiling point ofthe solvent used.

The alkylation of the compounds of the formula X with the compounds ofthe formula XI is preferably carried out with addition of a base.Suitable bases are, for example, the hydroxides, carbonates, acetates,hydrides or alkoxides of alkali metals such as lithium, sodium orpotassium or of alkaline earth metals such as magnesium or calcium. Itis also possible to employ mixtures of bases. In general, the base isemployed in equimolar amounts or in excess, for example in 1 to about 3times the molar amount of the compound of formula X. Particularlypreferably, the alkylation is carried out using potassium tert-butoxideor sodium hydride in dimethylformamide, or using sodium hydroxide inwater. The work-up of the reaction mixture can be carried out bystandard methods, and the product can be purified, if desired, bycustomary purification methods, for example by recrystallization orchromatography.

As already mentioned above, the radicals R^(1′), R^(1a′), R^(2′),R^(3′), R^(4′) and R^(5′) and also y in the compounds of the formulaeIa′ and Ie′ may have the meanings given in the definitions of R¹,R^(1a), R², R³, R⁴ and R⁵, so that the reaction products of the formulaeIa′ and Ie′ obtained by the illustrated synthesis processes alreadyconstitute compounds of the formulae Ia and Ie according to theinvention. However, it is also possible to carry out multifariousstructural modifications in the compounds of the formulae Ia′ and Ie′obtained by the synthesis processes illustrated. As already mentioned,this may be the liberation of functional groups which were present inprotected form during the synthesis.

However, it is also possible to introduce additional functional groupsby customary chemical methods into compounds of the formulae Ia′ and Ie′according to the invention, or to modify structural elements orfunctional groups which are present in compounds according to theinvention by customary methods. These methods are known to the personskilled in the art and are described in detail in standard works, forexample in Houben-Weyl, Methoden der Organischen Chemie, Thieme-Verlag,Stuttgart, or Organic Reactions, John Wiley & Sons, New York. Amodification of reaction conditions to the reactivity of the compoundsof the formulae Ia′ and Ie′ which may be necessary does not pose anyproblems to the person skilled in the art. The following reaction typesmay be mentioned as examples:

-   -   1. Hydrolysis of carboxylic esters to the carboxylic acids or        the alcohols    -   2. Conversion of carboxylic acids into the carboxylic esters by        esterification with alcohols in the presence of acid, conversion        of carboxylic acids into carboxamides (which are aminocarbonyl        compounds or carbamoyl compounds) or into carboxylic esters by        in situ activation of the carboxylic acids and reaction with        amines or alcohols or conversion of carboxylic acids into        reactive derivatives, for example into the carbonyl chlorides,        by reaction of the acids or salts thereof with chlorinating        agents, such as thionyl chloride, oxalyl chloride or phosphorus        halides, and reaction of the reactive derivatives with alcohols        and amines to give carboxylic esters and carboxamides.    -   3. Conversion of sulfonic acids or salts thereof into the        sulfonyl chlorides, for example with phosphorus halides, and        reaction of the sulfonyl chlorides with amines to give        sulfonamides.    -   4. Reduction of carboxylic acid derivatives to give aldehydes or        alcohols and reduction of aldehydes and ketones to alcohols, and        also addition of organometallic compounds, such as Grignard        reagents or organolithium compounds, to carboxylic acid groups        or aldehyde or ketone groups with formation of ketones or        alcohols.    -   5. Oxidation of alcohols to aldehydes or ketones.    -   6. Etherification, halogenation and esterification of alcohols.    -   7. Reduction of nitro compounds to amines.    -   8. Acylation of amines to carboxamides with carboxylic acids in        the presence of an activating agent or with reactive carboxylic        acid derivatives, such as carbonyl chlorides, and reaction of        amines with sulfonyl chlorides to give sulfonamides.    -   9. Nucleophilic substitutions at aliphatic carbon atoms, for        example reaction of halogen compounds with amines or mercaptans.    -   10. Electrophilic aromatic substitution with replacement of a        hydrogen atom at a carbocyclic or heterocyclic aromatic ring by        a functional group, for example halogenation, amino methylation,        formylation, acylation, sulfonation.

The starting materials of the formulae II and VII are known or can beprepared similarly to known compounds by well-known standard methodsdescribed in the literature. 1,3-dicarbonyl compounds of the formula IIare obtainable, for example, by ester condensations or by acylations ofβ-ketoesters with subsequent removal of the ester group. The aromaticsof the formula VII can be obtained, for example, by Friedel-Craftsacylations of furans, thiophenes and pyrroles with benzoic acidderivatives such as, for example, acyl chlorides. More details aboutthese reactions can be found in the standard works such as Houben-Weylor Organic Reactions (supra). The hydrazines of the formulae III and IXand the alkylating agents of the formula XI are also known, or they canbe prepared by well-known processes, details of which can be found inthese standard works.

The compounds of the formula I according to the invention effect anincrease of the cGMP concentration via the activation of the sGC, andthey are therefore useful agents for the therapy and prophylaxis ofdisorders which are associated with a low or decreased cGMP level orwhich are caused thereby, or for whose therapy or prophylaxis anincrease of the present cGMP level is desired. The activation of the sGCby the compounds of the formula I can be examined, for example, in theactivity assay described below, and their action on organs can beexamined, for example, by the determination of the relaxation of rataorta.

Disorders and pathological conditions which are associated with a lowcGMP level or in which an increase of the cGMP level is desired and forwhose therapy and prophylaxis it is possible to use compounds of theformula I are, for example, cardiovascular diseases, such as endothelialdysfunction, diastolic dysfunction, atherosclerosis, hypertension,stable and unstable angina pectoris, thromboses, restenoses, myocardialinfarction, strokes, coronary insufficiency or pulmonary hypertonia, or,for example, erectile dysfunction, asthma bronchiale, chronic kidneyinsufficiency and diabetes. Compounds of the formula I can additionallybe used in the therapy of cirrhosis of the liver and also, owing totheir partially synergistic action with the retrograde messengersubstance NO, for improving a restricted memory performance or abilityto learn.

The compounds of the formula I and their physiologically acceptablesalts can be administered to animals, preferably to mammals, and inparticular to humans as pharmaceuticals by themselves, in mixtures withone another or in the form of pharmaceutical preparations. The presentinvention therefore also provides the compounds of the formula I andtheir physiologically acceptable salts for use as pharmaceuticals, theiruse for normalizing a disturbed cGMP balance and in particular their usein the therapy and prophylaxis of the abovementioned syndromes, and alsotheir use for preparing medicaments for this purpose. Furthermore, thepresent invention provides pharmaceutical preparations which comprise asactive component an effective dose of at least one compound of theformula I and/or a physiologically tolerable salt thereof, in additionto customary pharmaceutically acceptable carriers and additives.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, lacquered tablets, sugar-coated tablets, granules,hard and soft gelatin capsules, aqueous, alcoholic or oily solutions,syrups, emulsions or suspensions, or rectally, for example in the formof suppositories. However, administration can also be carried outparenterally, for example subcutaneously, intramuscularly orintravenously in the form of solutions for injection or infusion. Othersuitable administration forms are, for example, percutaneous or topicaladministration, for example in the form of ointments, tinctures, spraysor transdermal therapeutic systems, or the inhalative administration inthe form of nasal sprays or aerosol mixtures, or, for example,microcapsules, implants or rods. The preferred administration formdepends, for example, on the disease to be treated and on its severity.

The pharmaceutical preparations usually comprise 0.5 to 90 percent byweight of the compounds of the formula I and/or their physiologicallyacceptable salts. The preparation of the pharmaceutical preparations canbe carried out in a manner known per se. For this purpose, one or morecompounds of the formula I and/or their physiologically acceptablesalts, together with one or more solid or liquid pharmaceutical carriersand/or auxiliaries and, if desired, in combination with otherpharmaceutically active compounds having therapeutic or prophylacticaction, are brought into a suitable administration form or dosage formwhich can then be used as a pharmaceutical in human or veterinarymedicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules, it is possible to use, for example, lactose, starch,for example maize starch, or starch derivatives, talc, stearic acid orits salts, etc. Carriers for soft gelatin capsules and suppositoriesare, for example, fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc.

Suitable carriers for the preparation of solutions, for example ofsolutions for injection, or of emulsions or syrups are, for example,water, saline, alcohols such as ethanol, glycerol, polyols, sucrose,invert sugar, glucose, mannitol, vegetable oils, etc. It is alsopossible to lyophilize the compounds of the formula I and theirphysiologically acceptable salts and to use the resulting lyophilisates,for example, for preparing preparations for injection or infusion.Suitable carriers for microcapsules, implants or rods are, for example,copolymers of glycolic acid and lactic acid.

Besides the active compounds and carriers, the pharmaceuticalpreparations can also contain customary additives, for example fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings or aromatizers, thickeners, diluents, buffer substances,furthermore solvents or solubilizers or agents for achieving a depoteffect, and salts for altering the osmotic pressure, coating agents orantioxidants.

The dosage of the active compound of the formula I to be administeredand/or of a physiologically acceptable salt thereof depends on theindividual case and is, as is customary, to be adapted to the individualcircumstances to achieve an optimum effect. Thus, it depends on thenature and the severity of the disorder to be treated, and also on thesex, age, weight and individual responsiveness of the human or animal tobe treated, on the efficacy and duration of action of the compoundsused, on whether the therapy is acute or chronic or prophylactic, or onwhether other active compounds are administered in addition to compoundsof the formula I.

In general, a daily dose of approximately 0.01 to about 100 mg/kg,preferably about 0.1 to about 10 mg/kg, in particular about 0.3 to about5 mg/kg (in each case mg per kg of bodyweight) are appropriate foradministration to an adult weighing approximately 75 kg in order toobtain effective results. The daily dose can be administered in a singledose or, in particular when larger amounts are administered, be dividedinto several, for example two, three or four individual doses. In somecases, depending on the individual response, it may be necessary todeviate upwards or downwards from the given daily dose. Pharmaceuticalpreparations normally contain about 0.2 to about 500 mg, preferablyabout 1 to about 200 mg, of active compound of the formula I and/or itsphysiologically acceptable salts per dose.

The compounds of the formula I activate the soluble guanylate cyclase.On account of this property, apart from use as pharmaceutically activecompounds in human medicine and veterinary medicine, they can also beemployed as a scientific tool or as aids for biochemical investigationsin which such an effect on guanylate cyclase is intended, and also fordiagnostic purposes, for example in the in vitro diagnosis of cell ortissue samples. The compounds of the formula I and salts thereof canfurthermore be employed, as already mentioned above, as intermediatesfor the preparation of other pharmaceutically active compounds.

The following examples illustrate embodiments of the invention, withoutlimiting the scope of the invention or its equivalents.

The abbreviations used in the description of the experiments are:

-   RT—Room temperature-   THF—Tetrahydrofuran-   DMF—Dimethylformamide

EXAMPLE 1

1-Benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt (startingmaterial)

1a) 5-(2-Fluorobenzoyl)furan-2-carboxylic acid: 132.6 g (0.53 mol) ofmethyl 5-(2-fluorobenzoyl)furan-2-carboxylate were introduced into asolution of 31.47 g (0.56 mol) of potassium hydroxide in 350 ml ofwater, and the mixture was heated to 70° C. After 1 h, the solution wasfiltered and acidified with conc. hydrochloric acid. The precipitate wasfiltered off with suction and recrystallized from ethanol. This gave106.3 g (85%) of the title compound. m.p.: 195-196° C.

1b) 1-Benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt: 70.26 g (0.3mol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid were initiallycharged in 350 ml of methanol, 109.95 g (0.9 mol) of benzylhydrazinewere added and the mixture was, after addition of 8 ml of glacial aceticacid, heated under reflux for 6 h. For work-up, the mixture wasconcentrated using a rotary evaporator, the residue was taken up in 2 Naqueous sodium hydroxide solution and extracted with ethyl acetate. Theaqueous phase was acidified with 2 N hydrochloric acid and extractedwith ethyl acetate. The residue that remained after drying andconcentration using a rotary evaporator was recrystallized from ethylacetate/n-hexane. The 68.3 g (0.20 mol) of5-(2-fluorobenzoyl)furan-2-carboxylic acid benzylhydrazone (m.p.: 147°C. (decomp.)) obtained in this manner were dissolved in 400 ml of DMF,45.38 g (0.40 mol) of potassium tert-butoxide were introduced and themixture was heated under reflux for 30 minutes. The precipitate wasfiltered off with suction, washed with dichloromethane andrecrystallized from ethanol/water (95:5). This gave 57.7 g (54%) of thetitle compound. The corresponding cyclization of the precursor which wasstill contained in the mother liquor gave 25.9 g of product. m.p.: >300°C.

¹H-NMR (D₆-DMSO): δ=5.73 (s, 2H, CH₂), 6.68 (d, 1H, H-3′), 6.92 (d, 1H,H-4′), 7.18-7.38 (m, 6H, phenyl-H, H-5), 7.45 (t, 1H, H-6), 7.75 (d, 1H,H-7), 8.18 (d, 1H, H-4).

EXAMPLE 2

1-Benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole (starting material): 52.4g (0.15 mol) of 1-benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt,were initially charged in 1250 ml of toluene, and after addition of 200ml of abs. ethanol and 50 ml of conc. sulfuric acid the mixture wasstirred under reflux on a water separator. After 3 hours, the mixturewas concentrated using a rotary evaporator, the oil that remained wastaken up in water/ethyl acetate and the aqueous phase was separated off.The organic phase was washed with water and 7.5% strength NaHCO₃solution, dried with sodium sulfate and concentrated. The residue wasrecrystallized from isopropanol. This gave 37.8 g (73%) of the titlecompound. m.p.: 98-99° C.

EXAMPLE 3

1-Benzyl-3-(5-hydroxymethyl-2-furyl)indazole (starting material): 2.06 g(54.6 mmol) of lithium aluminum hydride were initially charged in 250 mlof absolute THF, and a solution of 18.8 g (54.6 mmol) of1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole in 250 ml of THF was addeddropwise. After 45 min the mixture was admixed with 25% strengthpotassium carbonate solution and stirred at RT for 30 min and theprecipitate was filtered off with suction and washed with THF. Thecombined organic phases were concentrated using a rotary evaporator andthe residue was recrystallized from isopropanol. This gave 11.0 g (67%)of the title compound. m.p.: 113-114° C.

The following compounds were prepared correspondingly:

EXAMPLE 4

3-(5-Carboxy-2-furyl)-1-(3,5-bis(trifluoromethyl)phenyl)indazole

m.p.: 256-257° C.

EXAMPLE 5

3-(5-Ethoxycarbonyl-2-furyl)-1-(3,5-bis(trifluoromethyl)phenyl)indazole

m.p.: 128-129° C.

EXAMPLE 6

3-(5-Hydroxymethyl-2-furyl)-1-(3,5-bis(trifluoromethyl)phenyl)indazole

m.p.: 136-138° C.

EXAMPLE 7

1-Benzyl-3-(5-((2-hydroxyethoxy)carbonyl)-2-furyl)indazole: 200 mg (0.6mmol) of 1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole were dissolved inethylene glycol and heated under reflux for 1.5 h. For work-up, themixture was concentrated using a rotary evaporator and the crude productwas chromatographed over silica gel using hexane/ethyl acetate (1:1).This gave 68 mg (31%) of the title compound.

¹H-NMR (D₆-DMSO): δ=3.72 (q, 2H, CH ₂—OH), 4.31 (t, 2H, CH ₂—C—OH), 4.93(t, 1H, OH), 6.78 (s, 2H, CH ₂-phenyl), 7.23 (d, 1H, H-3′), 7.23-7.40(m, 6H, phenyl-H, H-5), 7.50 (d, 1H, H-4′), 7.50 (t, 1H, H-6), 7.83 (d,1H, H-7), 8.16 (d, 1H, H-4).

EXAMPLE 8

1-Benzyl-3-(5-methoxycarbonyl-2-furyl)-5-nitroindazole

8a) Methyl 5-(2-fluoro-5-nitrobenzoyl)furan-2-carboxylate: A solution of24.7 g (0.2 mol) of methyl furan-2-carboxylate in 50 ml of dried carbontetrachloride was added dropwise to a suspension of 2 g of iron(III)chloride and 29.0 g (0.14 mol) of 2-fluoro-5-nitrobenzoyl chloride in100 ml of dried carbon tetrachloride, and the mixture was heated underreflux (80° C.) for 14 h. 50 ml of methanol were subsequently added, themixture was stirred at RT for 30 min and concentrated using a rotaryevaporator. The residue that remained was taken up in ethyl acetate,washed with water and NaHCO₃ solution, dried with sodium sulfate,concentrated using a rotary evaporator and recrystallized fromisopropanol. This gave 3.5 g (9%) of the title compound. m.p.: 134-135°C.

8b) 1-Benzyl-3-(5-methoxycarbonyl-2-furyl)-5-nitroindazole: 2.6 g (9mmol) of methyl-5-(2-fluoro-5-nitrobenzoyl)furan-2-carboxylate and 3.31g (27 mmol) of benzylhydrazine were initially charged in approximately60 ml of methanol and, after addition of 0.2 ml of glacial acetic acid,heated to reflux for 15 min. The precipitate was filtered off withsuction, washed with a little methanol and dried at RT in a vacuumdrying cabinet. The crude product was purified by silica gelchromatography using dichloromethane. This gave 2.9 g (85%) of the titlecompound. m.p.: 171-173° C.

EXAMPLE 9

5-Amino-1-benzyl-3-(5-methoxycarbonyl-2-furyl)indazole: 0.9 g (2.4 mmol)of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-5-nitroindazole were dissolvedin 100 ml of methanol/THF (1:1) by gentle warming, a solution of 2.5 g(14.4 mmol) of sodium dithionite in 50 ml of water was added and themixture was stirred at RT for 16 h. For work-up, the mixture wasconcentrated and the residue was chromatographed over silica gel usingdichloromethane/methanol (98.5:1.5). This gave 140 mg (17%) of the titlecompound. m.p.: 195-196° C.

EXAMPLE 10

5-Amino-1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole: A solution of 80mg (0.23 mmol) of 5-amino-1-benzyl-3-(5-methoxycarbonyl-2-furyl)indazolein 5 ml of THF was added dropwise to 0.01 g (0.3 mmol) of lithiumaluminum hydride in 5 ml of THF, and the mixture was stirred at RT.After 3 h, 10 ml of a 25% strength K₂CO₃ solution were added andstirring was continued for 30 min. The precipitate was filtered off withsuction and extracted with boiling THF, the combined organic phases weredried and concentrated and the residue was chromatographed over silicagel using 95:5 dichloromethane/methanol. This gave 21 mg (29%) of thetitle compound. m.p.: 156° C.

EXAMPLE 11

1-Benzyl-3-(5-carboxy-2-furyl)-6-nitroindazole

11a) Methyl 5-(2-fluoro-4-nitrobenzoyl)furan-2-carboxylate: 8.4 g ofiron(III) chloride, 44.8 g (0.22 mol) of 2-fluoro-4-nitrobenzoylchloride and 33.4 g (0.26 mol) of methyl furan-2-carboxylate in 80 ml ofcarbon tetrachloride were heated under reflux for 2 days. For work-up,100 ml of methanol were added, the mixture was stirred for 10 min andthen concentrated, the residue was taken up in ethyl acetate/water andthe organic phase was extracted repeatedly with Na₂CO₃ solution. Theresidue that remained after drying and concentration of the ethylacetate phase was extracted with methanol, and the insoluble fractionwas chromatographed over silica gel using dichloromethane. This gave19.0 g (29%) of the title compound. m.p.: 136-138° C.

11b) 5-(2-Fluoro-4-nitrobenzoyl)furan-2-carboxylic acid: 14.5 g (49mmol) of methyl 5-(2-fluoro-4-nitrobenzoyl)furan-2-carboxylate wereadded to 200 ml of 0.1 N aqueous sodium hydroxide solution, and themixture was stirred at RT for 3 days. The mixture was subsequentlyadjusted to pH 4 using 1 N hydrochloric acid, cooled in an ice bath for30 min and filtered off with suction. This gave 8.6 g (62%) of the titlecompound. m.p.: 170° C. (decomp).

¹H-NMR (D₆-DMSO): δ=7.39 (d, 1H, H-4′), 7.50 (d, 1H, H-3′), 8.00 (dd,1H, H-6), 8.25 (dd, 1H, H-5), 8.34 (dd, 1H, H-3).

11c) 1-Benzyl-3-(5-carboxy-2-furyl)-6-nitroindazole: 8.5 g (30 mmol) of5-(2-fluoro-4-nitrobenzoyl)furan-2-carboxylic acid were dissolved in 100ml of methanol and admixed with 11.2 g (91 mmol) of benzylhydrazine, andthe mixture was heated under reflux for 7 h. The mixture wassubsequently poured into water, adjusted to pH 4 using conc.hydrochloric acid and extracted with ethyl acetate. The combined organicphases were dried and concentrated. For cyclization, the crudeintermediate was dissolved in 50 ml of DMF, 6.8 g (61 mmol) of potassiumtert-butoxide were added and the mixture was heated under reflux for 3h. For work-up, the mixture was concentrated, adjusted to pH 4 using 1 Nhydrochloric acid and extracted with ethyl acetate, the organic phasewas concentrated and the residue was chromatographed over silica gelusing ethyl acetate/glacial acetic acid (60:1). This gave 8 g(approximately 73%) of the title compound as an oil.

¹H-NMR (D₆-DMSO): δ=5.96 (s, 2H, CH₂), 7.22-7.41 (m, 7H, phenyl-H, H-3′,H-4′), 8.13 (dd, 1H, H-5), 8.38 (d, 1H, H-4), 8.93 (d, 1H, H-7).

EXAMPLE 12

3-(5-Carboxy-2-furyl)-1-(2-phenylethyl)indazole: 5 g (21 mmol) of5-(2-fluorobenzoyl)furan-2-carboxylic acid, 12 g (51 mmol) of(2-phenylethyl)hydrazinium sulfate and 8.4 g (102 mmol) of sodiumacetate in 50 ml of ethanol were boiled under reflux for 12 h. Themixture was subsequently concentrated and stirred with water/ethylacetate, and the ethyl acetate phase was separated off, dried andconcentrated. For purification, the crude intermediate (hydrazone) waschromatographed over silica gel using dichloromethane/methanol (9:1). 4g (11.3 mmol) of the hydrazone were dissolved in 20 ml of DMF and, with2.5 g (23 mmol) of potassium tert-butoxide, heated under reflux for 3 h.The precipitated potassium salt of the title acid was filtered off withsuction. The concentrated filtrate was chromatographed over silica gelusing dichloromethane/methanol (7:3). This gave a total of 1.9 g (27%,calculated for the acid) of the title compound.3-(5-carboxy-2-furyl)indazole was formed as a byproduct. m.p.:decomp. >190° C.

¹H-NMR (D₆-DMSO): δ=3.20 (t, 2H, CH ₂-phenyl), 4.65 (t, 2H, CH₂—N), 7.00(m, 2H, H-3′, H-4′), 7.13-7.23 (m, 6H, phenyl-H, H-5), 7.38 (t, 1H,H-6), 7.60 (d, 1H, H-7), 8.14 (d, 1H, H-4).

EXAMPLE 13

3-(5-Ethoxycarbonyl-2-furyl)-1-(2-phenylethyl)indazole: 0.8 g (2.4 mmol)of 3-(5-carboxy-2-furyl)-1-(2-phenylethyl)indazole were admixed with 25ml of ethanol, 150 ml of toluene and 2 ml of conc. sulfuric acid andheated on a water separator for 3 h. Silica gel chromatography usingdichloromethane/hexane (2:1) of the residue that was obtained afterconcentration using a rotary evaporator gave 400 mg (46%) of the titlecompound.

¹H-NMR (D₆-DMSO): δ=1.40 (t, 3H, CH₃), 3.34 (t, 2H, CH ₂-phenyl), 4.35(q, 2H, OCH₂), 4.73 (t, 2H, CH₂—N), 7.08-7.37 (m, 6H, phenyl-H, H-3′),7.38 (t, 1H, H-5), 7.45 (t, 1H, H-6), 7.48 (d, 1H, H-4′), 7.65 (d, 1H,H-7), 8.10 (d, 1H, H-4).

EXAMPLE 14

3-(5-Hydroxymethyl-2-furyl)-1-(2-phenylethyl)indazole: A solution of 300mg (0.83 mmol) of 3-(5-ethoxycarbonyl-2-furyl)-1-(2-phenylethyl)indazolein 10 ml of THF was added dropwise to 31.5 mg (0.83 mmol) of lithiumaluminum hydride in 10 ml of THF. After 1 h, the mixture was admixedwith 25% strength potassium carbonate solution and the precipitate wasseparated off and washed with THF. The combined THF filtrates were driedand concentrated. The crude product was purified by silica gelchromatography using dichloromethane/methanol (95:5). This gave 200 mg(75%) of the title compound.

¹H-NMR (D₆-DMSO): δ=3.20 (t, 2H, CH ₂-phenyl), 4.53 (bs, 2H, CH₂O), 4.66(t, 2H, CH₂—N), 6.50 (d, 1H, H-3′), 6.98 (d, 1H, H-4′), 7.15-7.27 (m,6H, phenyl-H, H-5), 7.38 (t, 1H, H-6), 7.58 (d, 1H, H-7), 8.08 (d, 1H,H-4).

EXAMPLE 15

3-(5-Carboxy-2-furyl)indazole: 2.5 g (11 mmol) of5-(2-fluorobenzoyl)furan-2-carboxylic acid, 3.28 g (24 mmol) ofbenzhydrazide and 2 drops of glacial acetic acid in 50 ml of ethanolwere heated under reflux for 10 h. The mixture was subsequentlyconcentrated using a rotary evaporator and the residue was taken up inwater, made alkaline using 2 N NaHCO₃ solution and extracted with ethylacetate. The aqueous phase was made acidic using 2 N hydrochloric acidand extracted with ethyl acetate. The combined organic phases were driedand concentrated using a rotary evaporator. The residue was dissolved in25 ml of THF, 2.74 g (24.2 mmol) of potassium tert-butoxide were addedand the mixture was stirred at reflux temperature for 1.5 h. Aftercooling, the mixture was concentrated using a rotary evaporator and theresidue was taken up in 1 N aqueous sodium hydroxide solution andextracted with ethyl acetate. The precipitate that resulted when theaqueous phase was acidified was filtered off with suction, washed withwater and dried in a vacuum drying cabinet at 40° C. This gave 1.88 g(75%) of the title compound. m.p.: 205° C. (decomp).

¹H-NMR (D₆-DMSO): δ=7.15 (d, 1H, H-3′), 7.28 (t, 1H, H-5), 7.40 (d, 1H,H-4′), 7.48 (t, 1H, H-6), 7.63 (d, 1H, H-7), 8.15 (d, 1H, H-4), 13.1(bs, 1H, COOH), 13.54 (bs, 1H, H-1).

EXAMPLE 16

3-(5-Ethoxycarbonyl-2-furyl)indazole: 1.75 g (7.7 mmol) of3-(5-carboxy-2-furyl)indazole together with 2.5 ml of concentratedsulfuric acid in 60 ml of toluene and 20 ml of ethanol were heated on awater separator. Customary work-up gave 1.2 g (60%) of the titlecompound.

¹H-NMR (D₆-DMSO): δ=1.36 (t, 3H, CH₃), 4.35 (q, 2H, CH₂), 7.10 (d, 1H,H-3′), 7.30 (t, 1H, H-5), 7.44 (t, 1H, H-6), 7.46 (d, 1H, H-4′), 7.64(d, 1H, H-7), 8.13 (d, 1H, H-4), 13.60 (bs, 1H, H-1).

EXAMPLE 17

1-((5-Chloro-2-thienyl)methyl)-3-(5-ethoxycarbonyl-2-furyl)indazole: 600mg (2.3 mmol) of 3-(5-ethoxycarbonyl-2-furyl)indazole together with 265mg (2.4 mmol) of potassium tert-butoxide were initially charged in 10 mlof DMF, 430 mg (2.6 mmol) of 2-chloro-5-(chloromethyl)thiophene in 1 mlof DMF were added dropwise and the mixture was stirred at RT for 2 h.Customary work-up gave 350 mg (41%) of the title compound. m.p.:124-126° C.

EXAMPLE 18

1-((5-Chloro-2-thienyl)methyl)-3-(5-hydroxymethyl-2-furyl)indazole: Thecompound was prepared similarly to Example 14 from1-((5-chloro-2-thienyl)methyl)-3-(5-ethoxycarbonyl-2-furyl)indazole byreduction with lithium aluminum hydride.

¹H-NMR (D₆-DMSO): δ=4.50 (d, 2H, CH₂O), 5.35 (t, 1H, OH), 5.88 (s, 2H,N—CH₂), 6.48 (d, 1H, thiophene-H-3), 6.98 (m, 2H, H-3′, thiophene-H-4),7.26 (t, 1H, H-5), 7.41 (d, 1H, H-4′), 7.48 (t, 1H, H-6), 7.81 (d, 1H,H-7), 8.10 (d, 1H, H-4).

EXAMPLE 19

1-Benzyl-3-(5-chlorocarbonyl-2-furyl)indazole: 15 g (0.05 mol) of1-benzyl-3-(5-carboxy-2-furyl)indazole and 36.43 g (0.31 mol) of thionylchloride in 400 ml of benzene were heated under reflux for 3 h. Thecooled mixture was filtered and concentrated. This gave 11.95 g(approximately 76%) of the title compound which was used for subsequentreactions without any further purification.

EXAMPLE 20

1-Benzyl-3-(5-(N-(4-trifluoromethylphenyl)carbamoyl)-2-furyl)indazole:0.29 g (1.8 mmol) of 4-trifluoromethylaniline were initially charged in20 ml of THF, 0.14 g (1.8 mmol) of pyridine were added and a solution of0.5 g (1.5 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10ml of THF was added dropwise at RT. After 0.5 h, the mixture was pouredinto ice-water and the precipitate was filtered off with suction andrecrystallized from isopropanol. This gave 0.47 g (69%) of the titlecompound. m.p.: 205-206° C.

Using processes similar to Example 20, the following compounds wereobtained:

EXAMPLE 21

1-Benzyl-3-(5-(N-phenylcarbamoyl)-2-furyl)indazole

m.p.: 138-143° C.

EXAMPLE 22

1-Benzyl-3-(5-(N-(4-chlorophenyl)carbamoyl)-2-furyl)indazole

m.p.: 202-205° C.

EXAMPLE 23

1-Benzyl-3-(5-(N-(4-nitrophenyl)carbamoyl)-2-furyl)indazole

m.p.: 204-208° C.

EXAMPLE 24

1-Benzyl-3-(5-(N-(2-naphthyl)carbamoyl)-2-furyl)indazole

m.p.: 167° C.

EXAMPLE 25

1-Benzyl-3-(5-(N-(2-thiazolyl)carbamoyl)-2-furyl)indazole

m.p.: 167-168° C.

EXAMPLE 26

1-Benzyl-3-(5-(N-(benzyloxy)carbamoyl)-2-furyl)indazole

m.p.: 140-143° C.

EXAMPLE 27

1-Benzyl-3-(5-(N-methyl-N-phenylcarbamoyl)-2-furyl)indazole

m.p.: 190° C.

EXAMPLE 28

1-Benzyl-3-(5-(N-(4-methoxyphenyl)carbamoyl)-2-furyl)indazole

m.p.: 175° C.

EXAMPLE 29

1-Benzyl-3-(5-(N-(2-hydroxyphenyl)carbamoyl)-2-furyl)indazole

m.p.: 196-197° C.

EXAMPLE 30

1-Benzyl-3-(5-(N-(2-hydroxyethyl)carbamoyl)-2-furyl)indazole: 0.23 g(3.7 mmol) of ethanolamine were initially charged in 20 ml of THF and asolution of 0.5 g (1.5 mmol) of1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was addeddropwise. After 0.75 h, the mixture was poured into ice-water and theprecipitate was filtered off with suction and recrystallized from ethylacetate. This gave 0.33 g (62%) of the title compound. m.p.: 119-127° C.

Using processes similar to Example 30, the following compounds wereobtained:

EXAMPLE 31

1-Benzyl-3-(5-(N-isopropylcarbamoyl)-2-furyl)indazole

m.p.: 156° C.

EXAMPLE 32

1-Benzyl-3-(5-(N-(n-propyl)carbamoyl)-2-furyl)indazole

m.p.: 152° C.

EXAMPLE 33

1-Benzyl-3-(5-(N-cyclohexylcarbamoyl)-2furyl)indazole

m.p.: 165° C.

EXAMPLE 34

1-Benzyl-3-(5-(N-benzylcarbamoyl)-2-furyl)indazole

m.p.: 113-124° C.

EXAMPLE 35

1-Benzyl-3-(5-(N-(2-dimethylaminoethyl)carbamoyl)-2-furyl)indazole

m.p.: 130° C.

EXAMPLE 36

1-Benzyl-3-(5-(N-(2-diisopropylaminoethyl)carbamoyl)-2-furyl)indazole

m.p.: 119-127° C.

EXAMPLE 37

1-Benzyl-3-(5-(N-(carbamoylmethyl)carbamoyl)-2-furyl)indazole

m.p.: 219-222° C.

EXAMPLE 38

1-Benzyl-3-(5-(N-(2-pyridylmethyl)carbamoyl)-2-furyl)indazole

m.p.: 160° C.

EXAMPLE 39

1-Benzyl-3-(5-carbamoyl-2-furyl)indazole: With simultaneous introductionof ammonia, a solution of 0.8 g (2.4 mmol) of1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was addeddropwise to 25 ml of a saturated solution of ammonia in THF. After 45min, the mixture was poured into ice-water and extracted with ethylacetate, and the organic phase was washed with 1 N hydrochloric acid,dried and concentrated using a rotary evaporator. The crude product wasrecrystallized from isopropanol. This gave 0.29 g (38%) of the titlecompound. m.p.: 259° C.

EXAMPLE 40

1-Benzyl-3-(5-(N-methylcarbamoyl)-2-furyl)indazole: 2.97 ml (5.94 mmol)of a 2 M solution of methylamine in THF were initially charged in 20 mlof THF, and a solution of 0.8 g (2.4 mmol) of1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was addeddropwise at RT. After 1 h, the mixture was poured into ice-water and theoil that separated off was extracted with ethyl acetate. The organicphase was washed with 1 N hydrochloric acid, dried and concentratedusing a rotary evaporator. The crude product was recrystallized fromisopropanol. This gave 0.44 g (55%) of the title compound.

m.p.: 182-183° C.

EXAMPLE 41

1-Benzyl-3-(5-formyl-2-furyl)indazole: 7.7 g (25.3 mmol) of1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and 11 g (126.5 mmol) ofactivated manganese(IV) oxide in 200 ml of dry carbon tetrachloride werestirred under reflux for 4.5 h. For work-up, the mixture was filteredoff with suction and the filtrate was washed with water, dried andconcentrated using a rotary evaporator. The crude product wasrecrystallized from isopropanol. This gave 4.8 g (63%) of the titlecompound. m.p.: 108° C.

EXAMPLE 42

1-Benzyl-3-(5-(1-hydroxypropyl)-2-furyl)indazole: At 10° C., 1.1 ml (1.1mmol) of a 1 M solution of ethylmagnesium bromide in THF were addeddropwise to 300 mg (0.99 mmol) of 1-benzyl-3-(5-formyl-2-furyl)indazolein 20 ml of diethyl ether. After 1 h at 10° C., the mixture was pouredinto ice-water and extracted with ethyl acetate, dried and concentrated.The crude product was purified by silica gel chromatography usingdichloromethane/methanol (95:5). This gave 200 mg (61%) of the titlecompound.

¹H-NMR (D₆-DMSO): δ=0.95 (t, 3H, CH₃), 1.80 (m, 2H, CH ₂—C—O), 4.55 (m,1H, CH—O), 5.36 (bs, 1H, OH), 5.78 (s, 2H, CH ₂-phenyl), 6.43 (d, 1H,H-3′), 6.94 (d, 1H, H-4′), 7.20-7.38 (m, 6H, phenyl-H, H-5), 7.45 (t,1H, H-6), 7.75 (d, 1H, H-7), 8.12 (d, 1H, H-4).

Using processes similar to Example 42, the following compounds wereobtained:

EXAMPLE 43

1-Benzyl-3-(5-(1-hydroxy-1-phenylmethyl)-2-furyl)indazole

m.p.: 138-139° C.

EXAMPLE 44

1-Benzyl-3-(5-(1-hydroxyprop-2-in-1-yl)-2-furyl)indazole

m.p.: 151° C.

EXAMPLE 45

1-Benzyl-3-(5-(1-hydroxy-1-methylethyl)-2-furyl)indazole: 3.0 g (8.7mmol) of 1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole were dissolved in100 ml of diethyl ether and a 3 M solution of methyl magnesium iodide indiethyl ether was added dropwise at 10° C. until the reaction had goneto completion. For work-up, the mixture was poured into ice-water andextracted with ethyl acetate, the combined organic phases were dried andconcentrated and the residue was recrystallized from ethyl acetate. Thisgave 0.9 g (31%) of the title compound. m.p.: 124-127° C.

EXAMPLE 46

1-Benzyl-3-(5-methoxycarbonyl-2-furyl)-5-methylpyrazole and isomer

46a) Methyl 5-(1,3-dioxobutyl)furan-2-carboxylate: Over a period of 90min, 130 g (0.5 mol) of tin(IV) chloride were added dropwise to amixture of 31.5 g (0.25 mol) of methyl furan-2-carboxylate and 102 g (1mol) of acetic anhydride which had been cooled to 0° C. After 16 h ofstirring at RT, the mixture was cooled to 0° C., 20 ml of 30% strengthhydrochloric acid were added dropwise and the mixture was subsequentlystirred at RT for 3 h. The resulting mixture was poured into 200 ml ofwater and extracted repeatedly with ethyl acetate. The combined organicextracts were washed with water, dried and concentrated. The residue waschromatographed over silica gel using dichloromethane. The main fractionwas recrystallized from isopropanol. This gave 19 g (36%) of the titlecompound. m.p.: 111-112° C.

46b) 1-Benzyl-3-(5-methoxycarbonyl-2-furyl)-5-methylpyrazole and isomer:8 g (38.1 mmol) of methyl 5-(1,3-dioxobutyl)furan-2-carboxylate, 5.1 g(41.9 mmol) of benzylhydrazine and 1 ml of acetic acid in 150 ml ofethanol were heated under reflux for 2 h. For work-up, the mixture wasconcentrated, the residue was taken up in methylene chloride and thesolution was washed with 2 N aqueous sodium hydroxide solution, driedwith sodium sulfate and concentrated. The oil that remained crystallizedovernight and was recrystallized from a little isopropanol. This gave7.95 g (70%) of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-5-methylpyrazoleas a mixture with the isomeric1-benzyl-5-(5-methoxycarbonyl-2-furyl)-3-methylpyrazole. m.p.: 65-66° C.

EXAMPLE 47

1-Benzyl-3-(2-furyl)-5-trifluoromethylpyrazole: 10 g (48.5 mmol) of4,4,4-trifluoro-1-(2-furyl)-1,3-butadione, 7.5 g (53.4 mmol) ofbenzylhydrazine and 0.5 ml of acetic acid in 75 ml of ethanol wereheated under reflux for 2 h. The mixture was concentrated, the residuewas dissolved in dichloromethane, the solution was extracted alkalineand the organic phase was subsequently dried and concentrated. Theresidue was purified over silica gel using n-hexane/ethyl acetate (5:1).This gave 9.0 g (64%) of 1-benzyl-5-(2-furyl)-3-trifluoromethylpyrazole,in addition to 4.0 g of uncyclized hydrazone. This hydrazone wasdissolved in 200 ml of methanol and heated under reflux with 1 ml ofconc. sulfuric acid for 2 h. The mixture was subsequently concentrated,admixed with water and extracted with dichloromethane, and the organicphase was dried and concentrated once more. This gave 3.1 g (22%) of1-benzyl-3-(2-furyl)-5-trifluoromethylpyrazole.

¹H-NMR (D₆-DMSO): δ=5.51 (s, 2H, CH₂), 6.60 (dd, 1H, H-4′), 6.92 (d, 1H,H-3′), 7.10-7.43 (m, 6H, phenyl-H, H-4), 7.75 (d, 1H, H-5′).

EXAMPLE 48

1-Benzyl-3-(5-formyl-2-furyl)-5-trifluoromethylpyrazole: 10 ml of dryDMF were initially charged at 10° C., 1.9 g (12.4 mmol) of phosphorusoxychloride were added dropwise and the mixture was stirred for 30 min.A solution of 3 g (10.3 mmol) of1-benzyl-3-(2-furyl)-5-trifluoromethylpyrazole in 10 ml of DMF was addeddropwise, and the mixture was stirred at RT overnight. The mixture waspoured into ice-water and adjusted to pH 9 using potassium carbonatesolution. The precipitated product was filtered off with suction anddried in a vacuum drying cabinet at 50° C. This gave 3.3 g (100%) of thetitle compound. m.p.: 76.5-77.5° C.

EXAMPLE 49

1-Benzyl-3-(5-hydroxymethyl-2-furyl)-5-trifluoromethylpyrazole: 3 g(9.36 mmol) of 1-benzyl-3-(5-formyl-2-furyl)-5-trifluoromethylpyrazolewere dissolved in 80 ml of methanol, 0.35 g (9.36 mmol) of sodiumborohydride were added in portions and the mixture was stirred at RT for1 h. The mixture was subsequently concentrated, the residue was admixedwith water and methylene chloride, the methylene chloride phase wasseparated off, dried and concentrated and the residue waschromatographed over silica gel using dichloromethane. This gave 1.6 g(53%) of the title compound.

¹H-NMR (D₆-DMSO): δ=4.43 (d, 2H, CH₂O), 5.30 (t, 1H, OH), 5.52 (s, 2H,CH₂-phenyl), 6.41 (d, 1H, H-4′), 6.83 (d, 1H, H-3′), 7.13-7.21 (m, 2H,phenyl-H), 7.25 (s, 1H, H-4), 7.30-7.43 (m, 3H, phenyl-H).

EXAMPLE 50

3-(5-Carboxy-2-furyl)-1-(4-trifluoromethylpyrimidin-2-yl)indazolehydrochloride: 1.3 g (5.7 mmol) of 3-(5-carboxy-2-furyl)indazoletogether with 1.3 g (11.4 mmol) of potassium tert-butoxide weredissolved in 5 ml of dry DMF and admixed with2-chloro-4-trifluoromethylpyrimidine dissolved in 5 ml of DMF. Themixture was stirred at 60° C. the hydrochloride was precipitated fromthe aqueous phase by addition of 1 N hydrochloric acid. This gave 420 mg(25%) of the title compound. m.p.: 258-261° C.

Pharmacological Investigations

1. Activation of the Soluble Guanylate Cyclase

The activation of the sGC, which catalyzes the conversion of GTP intocyclic guanosine monophosphate cGMP and pyrophosphate, by the compoundsaccording to the invention was quantified with the aid of an enzymeimmunoassay “EIA” from Amersham. For this purpose the substances to betested were initially incubated with sGC in microtiter plates, and theamount of the cGMP formed was then determined.

The sGC which was employed had been isolated from bovine lung (seeMethods in Enzymology, Volume 195, p. 377). The test solutions (100 μlper well) contained 50 mM triethanolamine “TEA” buffer (pH 7.5), 3 mMMgCl₂, 3 mM reduced glutathione “GSH,” 0.1 mM GTP, 1 mM3-isobutyl-1-methylxanthine “IBMX,” suitably diluted enzyme solution andthe substance to be tested or, in the control experiments, the solvent.The substances to be tested were dissolved in dimethyl sulfoxide “DMSO”and the solution was diluted with DMSO/water, so that the finalconcentration of the substance to be tested in the test solution was 50μM. The DMSO concentration in the test solution was 5% (v/v). Thereaction was initiated by addition of the sGC. The reaction mixture wasincubated at 37° C. for 15 to 20 minutes and then stopped by ice-coolingand addition of the stop reagent (50 mM EDTA, pH 8.0). An aliquot of 50μl was taken and used for determining the cGMP content using theacetylation protocol of the Amersham cGMP-EIA kit. The absorption of thesamples was measured at 450 nm (reference wavelength 620 nm) in amicrotiter plate reader. The cGMP concentration was determined using astandard curve which was obtained under the same test conditions. Theactivation of sGC by a test substance is reported as the n-foldstimulation of the basal enzyme activity which was found in the controlexperiments (using solvent instead of test substance). This iscalculated using the formula:n-fold stimulation=[cGMP]_(test substance)/[cGMP]_(control).

The following values were determined:

Compound Concentration n-fold stimulation Example 6 10 μM 3.3-foldExample 7 100 μM 5.5-fold Example 21 100 μM   3-fold Example 25 10 μM2.8-fold Example 40 100 μM 2.4-fold Example 44 100 μM 3.2-fold2. Relaxation of Rat Aorta

For this test, normotensive male Wistar-Kyoto rats were sacrificed by ablow to the neck. The abdominal cavity and the thorax were opened by amedium sternotomy. The descending aorta was subsequently removed, freedof connective tissue and divided into 8 rings of a length ofapproximately 4 mm. The tip of a pair of tweezers was introduced intothe lumen of 4 of the 8 rings. The endothelium was removed by carefullyrolling the rings over the tip of the pair of tweezers. All 8 aortarings (4 with endothelium and 4 without endothelium) were subsequentlysuspended in an organ bath (Schuler-Organbad; Hugo Sachs Elektronik) ata constant temperature of 37° C. for the isometric determination of thecontractile tone. For 30 minutes, the rings were calibrated at a restingtension of 1 g in carbonated (95% O₂; 5% CO₂) Krebs-Henseleit solution(composition: Na⁺ 144.0 mM; K⁺ 5.9 mM; Cl⁻ 126.9 mM; Ca²⁺ 1.6 mM; Mg²⁺1.2 mM; H₂PO₄ ⁻ 1.2 mM; SO₄ ²⁻ 1.2 mM; HCO₃ ⁻ 25.0 mM; D-glucose 11.1mM) of pH 7.4. Additionally, 1 μmol/l of indomethacin were added to theKrëbs-Henseleit solution to inhibit prostaglandin biosynthesis. Therings were subsequently precontracted by addition of phenylephrine(concentration in the solution: 1 μM) and the endothelium-dependentrelaxation or the functional loss of the endothelium was tested byaddition of acetylcholine (concentration in the solution: 1 μM). After a30-minute washing period, the rings were then again precontracted byaddition of phenylephrine (1 μM), and the relaxing action of the testsubstances of the formula I was determined by administration ofcumulative doses of the latter. The data were evaluated by standardmethods. Reported is the concentration IC₅₀ by which contraction isinhibited by 50% (50% relaxation).

The following values were determined:

Compound IC₅₀ Example 40 Ring with endothelium 2.4 μM Example 40 Ringwithout endothelium 0.2 μM

The above embodiments and description are included to illustrate theinvention, and are not intended to express or imply any limits upon thescope of the invention, nor of its equivalents.

1. A compound of the formula I

in which X is O; R¹ is halogen, OR⁶, NR⁷R⁸, CO—OR⁹, CO—R¹⁰, CO—NR¹¹R¹²,CO—NR¹²—OR¹¹, S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵, CN, (C₁-C₁₀)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R¹ are in each case unsubstituted or substituted by one ormore substituents R⁵; and R^(1a) is hydrogen, halogen, OR⁶, NR⁷R⁸,CO—OR⁹, CO—R¹⁰, CO—NR¹¹R¹², CO—NR¹²—OR¹¹, S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵,CN, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, orHet-(C₁-C₄)-alkyl, where alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, Het, and Het-alkyl representing R^(1a) are in each caseunsubstituted or substituted by one or more substituents R⁵; and R² andR³ are identical or different, and are hydrogen, (C₁-C₁₀)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R² or R³ are unsubstituted or substituted by one or moresubstituents R⁵; R⁴ is hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R⁴ are unsubstituted or substituted by one or moresubstituents R⁵, and where n is 0, R⁴ is not hydrogen; n is 0, 1 or 2;Het is a 5- to 7-membered, saturated, or unsaturated heterocycle; R⁵ ishalogen, (C₁-C₅)-alkyl, OR⁶, NR⁷R⁸, CO—OR⁹, CO—R¹⁰, CO—NR¹¹R¹²,CO—NR¹²—R¹¹, S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵, NO₂, CN, or CF₃, whereradicals R⁵ that occur more than once are identical or different; R⁶,R⁷, R⁸, R¹¹, and R¹⁴ are identical or different, and are hydrogen,(C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het,Het-(C₁-C₄)-alkyl, CO—R¹⁶, or S(O)₂—R¹⁷, where alkyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, Het, and Het-alkyl representing R⁶, R⁷, R⁸,R¹¹, and R¹⁴ are in each case unsubstituted or substituted by one ormore identical or different substituents selected from the groupconsisting of halogen, (C₁-C₅)-alkyl, OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²²,CO—NR²³R²⁴, CO—NR²⁴—R²³, S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷, NO₂, CN, and CF₃,and where radicals R⁶, R⁷, R⁸, R¹¹, and R¹⁴ that occur more than onceare identical or different; R⁹, R¹⁰, R¹², R¹³ and R¹⁵ are identical ordifferent, and are hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R⁹, R¹⁰, R¹², R¹³, and R¹⁵ are in each case unsubstitutedor substituted by one or more identical or different substituentsselected from the group consisting of halogen, (C₁-C₅)-alkyl, OR¹⁸,NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴, CO—NR²⁴—R²³, S(O)_(m)—R²⁵,S(O)₂—NR²⁶R²⁷, NO₂, CN, and CF₃, and where radicals R⁹, R¹⁰, R¹², R¹³,and R¹⁵ that occur more than once are identical or different; or tworadicals R⁷ with R⁸, two radicals R¹¹ with R¹², or two radicals R¹⁴ withR¹⁵, in each case together with the nitrogen atom which carries the tworadicals, form a 5- to 7-membered, saturated or unsaturated heterocyclicring which further comprises zero or one additional ring heteroatomselected from the group consisting of nitrogen, oxygen and sulfur, andthe heterocyclic ring is unsubstituted or substituted by one or moreidentical or different substituents selected from the group consistingof (C₁-C₄)-alkyl and halogen; R¹⁶ is hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl; R¹⁷ is(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl;R¹⁸, R¹⁹, R²⁰, R²³ and R²⁶ are identical or different, and are hydrogen,(C₁-C₁₀)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, the radical Het, the radicalHet-(C₁-C₄)-alkyl, CO—R¹⁶ or S(O)₂—R¹⁷, where radicals R¹⁸, R¹⁹, R²⁰,R²³, and R²⁶ that occur more than once are identical or different; R²¹,R²², R²⁴, R²⁵ and R²⁷ are identical or different, and are hydrogen,(C₁-C₁₀)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl,where radicals R²¹, R²², R²⁴, R²⁵, and R²⁷ that occur more than once areidentical or different; or two radicals R¹⁹ with R²⁰, two radicals R²³with R²⁴, or two radicals R²⁶ with R²⁷, in each case together with thenitrogen atom which carries the two radicals, form a 5- to 7-membered,saturated or unsaturated heterocyclic ring which further comprises zeroor one additional ring heteroatom selected from the group consisting ofnitrogen, oxygen and sulfur, and the heterocyclic ring is unsubstitutedor substituted by one or more identical or different substituentsselected from the group consisting of (C₁-C₄)-alkyl and halogen; m is 0,1 or 2; a stereoisomer of the compound of formula I, or aphysiologically acceptable salt of any of the forgoing.
 2. The compoundof the formula I as claimed in claim 1, in which R^(1a) is hydrogen, astereoisomer thereof, or a physiologically acceptable salt of any of theforegoing.
 3. The compound of the formula I as claimed in claim 1, inwhich R¹ is (C₁-C₁₀)-alkyl which is substituted by hydroxyl, or isCO—OR⁹ or is CO—NR¹¹R¹², a stereoisomer thereof, or a physiologicallyacceptable salt of any of the foregoing.
 4. The compound of the formulaI as claimed in claim 1, in which R¹¹ is hydrogen and R¹² isunsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl which is substituted by aradical selected from the group consisting of OR¹⁸, NR¹⁹R²⁰ andCO—NR²³R²⁴, 5- or 6-membered heteroaryl, unsubstituted phenyl or phenylwhich is substituted by one, two or three identical or differentradicals selected from the group consisting of halogen, (C₁-C₅)-alkyl,OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴, S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷,NO₂, CN and CF₃, a stereoisomer thereof, or a physiologically acceptablesalt of any of the foregoing.
 5. A process for preparing a compound offormula I as claimed in claim 1, which comprises: reacting a1,3-dicarbonyl compound of formula II, or a salt thereof, with ahydrazine of formula III, or a salt thereof,

where in the formulae II and III, radicals X, R^(1′), R^(1a′) and R^(4′)and the number n are the same as X, R¹, R^(1a), R⁴ and n, respectively,given in formula I; and radicals R^(2′) and R^(3′) are the same as R²and R³, respectively, given in formula I, except that R^(2′) and R^(3′)are not an aromatic ring together with the carbon atoms which carrythem; to obtain a compound of formula I.
 6. The process for preparing acompound of formula I as claimed in claim 5, where in the fomulae II andIII, radicals R^(1′), R^(1a′), R^(2′), R^(3′) and R^(4′) are present ina protected form or in a precursor form of radicals R¹, R^(1a), R², R³,and R⁴, respectively, as defined in formula I; further comprising thestep of converting the radicals R^(1′), R^(1a′), R^(2′), R^(3′) andR^(4′) into the radicals R¹, R^(1a), R², R³ and R⁴, respectively, toobtain a compound of formula I.
 7. A pharmaceutical composition,comprising an efficacious amount of one or more compounds of formula Ias claimed in claim 1, a mixture of two or more stereoisomers thereof,or a physiologically acceptable salt of any of the foregoing, togetherwith at least one pharmaceutically acceptable carrier.
 8. A method ofactivating soluble guanylate cyclase in a human or animal patient inneed of such activation, comprising administering to the patient anefficacious amount of at least one compound of formula I

in which X is O; R¹ and R^(1a) are identical or different, and arehydrogen, halogen, OR⁶, NR⁷R⁸, CO—OR⁹, CO—R¹⁰, CO—NR¹¹R¹², CO—NR¹²—R¹¹,S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵, CN, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R¹ or R^(1a) are in each case unsubstituted or substitutedby one or more substituents R⁵; and R² and R³ are identical ordifferent, and are hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R² or R³ are unsubstituted or substituted by one or moresubstituents R⁵; R⁴ is hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R⁴ are unsubstituted or substituted by one or moresubstituents R⁵ and where n is 0, R⁴ is not hydrogen; n is 0, 1 or 2;Het is a 5- to 7-membered, saturated, or unsaturated heterocycle; R⁵ ishalogen, (C₁-C₅)-alkyl, OR⁶, NR⁷R⁸, CO—OR⁹, CO—R¹⁰, CO—NR¹¹R¹²,CO—NR¹²—OR¹¹, S(O)_(m)—R¹³, S(O)₂—NR¹⁴R¹⁵, NO₂, CN, or CF₃, whereradicals R⁵ that occur more than once are identical or different; R⁶,R⁷, R⁸, R¹¹, and R¹⁴ are identical or different, and are hydrogen,(C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het,Het-(C₁-C₄)-alkyl, CO—R¹⁶, or S(O)₂—R¹⁷, where alkyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, Het, and Het-alkyl representing R⁶, R⁷, R⁸,R¹¹, and R¹⁴ are in each case unsubstituted or substituted by one ormore identical or different substituents selected from the groupconsisting of halogen, (C₁-C₅)-alkyl, OR¹⁸, NR¹⁹R²⁰, CO—OR²¹, CO—R²²,CO—NR²³R²⁴, CO—NR^(24—R) ²³, S(O)_(m)—R²⁵, S(O)₂—NR²⁶R²⁷, NO₂, CN, andCF₃, and where radicals R⁶, R⁷, R⁸, R¹¹, and R¹⁴ that occur more thanonce are identical or different; R⁹, R¹⁰, R¹², R¹³ and R¹⁵ are identicalor different, and are hydrogen, (C₁-C₁₀)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl, wherealkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, Het, and Het-alkylrepresenting R⁹, R¹⁰, R¹², R¹³, and R¹⁵ are in each case unsubstitutedor substituted by one or more identical or different substituentsselected from the group consisting of halogen, (C₁-C₅)-alkyl, OR¹⁸,NR¹⁹R²⁰, CO—OR²¹, CO—R²², CO—NR²³R²⁴, CO—NR^(24—R) ²³, S(O)_(m)—R²⁵,S(O)₂—NR²⁶R²⁷, NO₂, CN, and CF₃, and where radicals R⁹, R¹⁰, R¹², R¹³,and R¹⁵ that occur more than once are identical or different; or tworadicals R⁷ with R⁸, two radicals R¹¹ with R¹², or two radicals R¹⁴ withR¹⁵, in each case together with the nitrogen atom which carries the tworadicals, form a 5- to 7-membered, saturated or unsaturated heterocyclicring which further comprises zero or one additional ring heteroatomselected from the group consisting of nitrogen, oxygen and sulfur, andthe heterocyclic ring is unsubstituted or substituted by one or moreidentical or different substituents selected from the group consistingof (C₁-C₄)-alkyl and halogen; R¹⁶ is hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl; R¹⁷ is(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl;R¹⁸, R¹⁹, R²⁰, R²³ and R²⁶ are identical or different, and are hydrogen,(C₁-C₁₀)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, the radical Het, the radicalHet-(C₁-C₄)-alkyl, CO—R¹⁶ or S(O)₂—R¹⁷, where radicals R¹⁸, R¹⁹, R²⁰,R²³, and R²⁶ that occur more than once are identical or different; R²¹,R²², R²⁴, R²⁵ and R²⁷ are identical or different, and are hydrogen,(C₁-C₁₀)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, Het, or Het-(C₁-C₄)-alkyl,where radicals R²¹, R²², R²⁴, R²⁵, and R²⁷ that occur more than once areidentical or different; or two radicals R¹⁹ with R²⁰, two radicals R²³with R²⁴, or two radicals R²⁶ with R²⁷, in each case together with thenitrogen atom which carries the two radicals, form a 5- to 7-membered,saturated or unsaturated heterocyclic ring which further comprises zeroor one additional ring heteroatom selected from the group consisting ofnitrogen, oxygen and sulfur, and the heterocyclic ring is unsubstitutedor substituted by one or more identical or different substituentsselected from the group consisting of (C₁-C₄)-alkyl and halogen; m is 0,1 or 2; a stereoisomer of the compound of formula I, a mixture of two ormore stereoisomers of the compound of formula I, or a physiologicallyacceptable salt of any of the forgoing.
 9. The method of claim 8, inwhich the patient is administered an efficacious amount of at least onecompound of formula I, a stereolsomer thereof, a mixture of two or morestereoisomers thereof, or a physiologically acceptable salt of any ofthe foregoing, to prevent cardiovascular disease, endothelialdysfunction, diastolic dysfunction, atherosclerosis, hypertension,angina pectoris, thromboses, restenoses, myocardial infarction, stroke,cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, orchronic kidney insufficiency.
 10. The method of claim 8, in which thepatient is administered an efficacious amount of at least one compoundof formula I, a stereolsomer thereof, a mixture of two or morestereoisomers thereof, or a physiologically acceptable salt of any ofthe foregoing, to treat cardiovascular disease, endothelial dysfunction,diastolic dysfunction, atherosclerosis, hypertension, angina pectoris,thromboses, restenoses, myocardial infarction, stroke, cardiacinsufficiency, pulmonary hypertonia, erectile dysfunction, asthmabronchiale, chronic kidney insufficiency, diabetes, cirrhosis of theliver, restricted memory performance, or learning disability.
 11. Amethod of preventing cardiovascular disease, endothelial dysfunction,diastolic dysfunction, atherosclerosis, hypertension, angina pectoris,thromboses, restenoses, myocardial infarction, stroke, cardiacinsufficiency, pulmonary hypertonia, erectile dysfunction, or chronickidney insufficiency, in which the patient is administered anefficacious amount of at least one compound of the formula I as claimedin claim 1, a stereoisomer thereof, a mixture of two or morestereoisomers of the compound of formula I, or a physiologicallyacceptable salt of any of the foregoing.
 12. A method of treatingcardiovascular disease, endothelial dysfunction, diastolic dysfunction,atherosclerosis, hypertension1 angina pectoris, thromboses, restenoses,myocardial infarction, stroke, cardiac insufficiency, pulmonaryhypertonia, erectile dysfunction, asthma bronchiale, chronic kidneyinsufficiency, diabetes, cirrhosis of the liver, restricted memoryperformance, or learning disability, in which the patient isadministered an efficacious amount of at least one compound of theformula I as claimed in claim 1, a stereoisomer thereof, a mixture oftwo or more stereoisomers of the compound of formula I, or aphysiologically acceptable salt of any of the foregoing.
 13. Thecompound 1-benzyl-3-(2-furyl)-5-trifluoromethylpyrazole, a stereoisomerthereof, or a physiologically acceptable salt of any of the foregoing.